Methods of using a bispecific antibody that recognizes coagulation factor ix and/or activated coagulation factor ix and coagulation factor x and/or activated coagulation factor x

ABSTRACT

An objective of the present invention is to provide an effective pharmaceutical composition or a dosage regimen for preventing and/or treating bleeding, a disease accompanying bleeding, or a disease caused by bleeding. The inventors discovered that by administering a pharmaceutical composition comprising a bispecific antigen-binding molecule that recognizes (a) blood coagulation factor IX and/or activated blood coagulation factor IX and (b) blood coagulation factor X and/or activated blood coagulation factor X according to a given dosage regimen, bleeding, a disease accompanying bleeding, or a disease caused by bleeding can be prevented and/or treated more effectively.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application is a divisional application of U.S. applicationSer. No. 17/828,752, filed May 31, 2022, which is a divisionalapplication of U.S. application Ser. No. 16/330,269, filed Mar. 4, 2019(now U.S. Pat. No. 11,352,438), which is the National Stage ofInternational Application No. PCT/JP2017/031933, filed Sep. 5, 2017,which claims the benefit of U.S. Provisional Application No. 62/383,933filed Sep. 6, 2016, U.S. Provisional Application No. 62/437,281 filedDec. 21, 2016, and U.S. Provisional Application No. 62/485,514 filedApr. 14, 2017. The entire disclosures of these applications are herebyincorporated by reference.

SEQUENCE LISTING

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TECHNICAL FIELD

The present invention relates generally to the field of therapeutics forbleeding disorders.

BACKGROUND ART

Hemophilia is a hemorrhagic disease caused by a congenital deficiency ordysfunction of coagulation factor VIII (FVIII) or coagulation factor IX(FIX). The former is called hemophilia A and the latter is calledhemophilia B. Genes for both factors are located on the X chromosome,and since genetic defects take the X-chromosome-linked recessivehereditary form, 99% or more of the patients who develop the disease aremen. It is known that the prevalence rate is approximately one in 10,000live male births, and the ratio between hemophilia A and hemophilia B isapproximately 5:1.

The severity of hemophilia A is defined by the FVIII activity in blood.Patients with an activity of less than 1% are classified as severe,patients with an activity of 1% to 5% are classified as moderate, andpatients with an activity of more than 5% and less than 40% areclassified as mild. Severe patients who account for approximately halfof hemophilia A patients exhibit bleeding symptoms several times amonth, and this frequency is markedly high as compared to those ofmoderate and mild patients.

For bleeding in hemophilia A patients, FVIII formulations are generallyadministered on demand (on-demand therapy). In recent years, FVIIIformulations are also administered prophylactically to prevent bleedingevents (regular replacement therapy; NPLs 1 and 2). The half-life ofFVIII formulations in blood is approximately 8 to 19 hours. Therefore,for continuous prevention, FVIII formulations are administered topatients three times a week (NPLs 3 and 4). In on-demand therapy, FVIIIformulations are also additionally administered at regular intervals asnecessary to prevent reoccurrence of bleeding. In addition, FVIIIformulations are mainly administered at home, but since they areadministered intravenously, the difficulty of securing a blood vessel isa problem. Therefore, there has been a strong need for pharmaceuticalagents with a lesser burden regarding their administration as comparedto FVIII formulations.

Occasionally, antibodies against FVIII (inhibitors) develop inhemophilia A patients. Such inhibitors counteract the effects of theFVIII formulations. For bleeding in patients who have developedinhibitors (inhibitor patients), bypassing agents are administered.Their mechanisms of action are not dependent on FVIII function, that is,on the function of catalyzing the activation of blood coagulation factorX (FX) by activated blood coagulation factor IX (FIXa). Therefore, insome cases, bypassing agents cannot sufficiently stop the bleeding.Recently, results suggesting the effectiveness of regular administrationtherapy of bypassing agents have been obtained, but this has not yieldeda sufficient effect to suppress bleeding as compared to FVIIIformulations. Accordingly, there has been a strong need for therapeuticagents that can be administered subcutaneously, as well as long-actingtherapeutic agents that can be administered less frequently, regardlessof the presence of inhibitors.

Recently, as a means for solving the problem, an antibody thatfunctionally substitutes for FVIII, emicizumab (ACE910, R05534262) andits use were disclosed (PTLs 1, 2, 3, 4, and 5, NPLs 5, 6, 7, and 8).

Emicizumab is a recombinant humanized bispecific antibody that binds to(a) FIX and/or FIXa and (b) FX and/or activated blood coagulation factorFX (FXa), and mimics the cofactor function of FVIII. Japanese patientswith severe hemophilia A (with or without factor VIII inhibitors) wereenrolled in an open-label, non-randomized, inter-individualdose-escalation study of emicizumab. Enrolled patients were assigned tocohort 1, cohort 2, or cohort 3, and received subcutaneous emicizumab atan initial dose of 1.0 mg per kilogram of body weight (cohort 1) or 3 mgper kilogram (cohorts 2 and 3) at week 0 (day 1), followed by aonce-weekly subcutaneous dose of 0.3, 1.0, or 3 mg per kilogram (cohorts1, 2, and 3, respectively) from week 1 through week 12. The initial andsubsequent doses for cohort 3 were the same. Emicizumab decreased theannualized bleeding rates (ABR) in patients who had hemophilia A with orwithout factor VIII inhibitors (NPL 9). At the completion of the 12-weekstudy, eligible patients were able to participate in an extension study(NPL 10).

CITATION LIST Patent Literature

-   [PTL 1] WO 2005/035754-   [PTL 2] WO 2005/035756-   [PTL 3] WO 2006/109592-   [PTL 4] WO 2012/067176-   [PTL 5] WO 2015/194233

Non-Patent Literature

-   [NPL 1] Blood 58, 1-13 (1981)-   [NPL 2] Nature 312, 330-337 (1984)-   [NPL 3] Nature 312, 337-342 (1984)-   [NPL 4] Biochim. Biophys. Acta 871, 268-278 (1986)-   [NPL 5] Nature Medicine 18, 1570-1574(2012)-   [NPL 6] PLOS ONE 8, 1-13(2013)-   [NPL 7] J Thromb Haemost. 12, 206-213(2014)-   [NPL 8] Blood 127(13), 1633-1641(2016)-   [NPL 9] N Engl J Med. 374(21), 2044-2053(2016)-   [NPL 10] XXV Congress of the International Society on Thrombosis and    Haemostasis, Toronto, Canada, Jun. 20-25, 2015. Abstr AS017.

SUMMARY OF INVENTION Technical Problem

An objective of the present invention is to provide another effectivepharmaceutical composition or a dosage regimen for treating and/orreducing the incidence of a disease that develops and/or progresses dueto a decrease or deficiency in the activity of FVIII and/or activatedblood coagulation factor VIII (FVIIIa).

Solution to Problem

As a result of dedicated research, the present inventors succeeded indiscovering an effective dosage regimen for a pharmaceutical compositioncontaining a bispecific antigen-binding molecule (antibody) thatrecognizes (a) FIX and/or FIXa and (b) FX and/or FXa for treating and/orreducing the incidence of a disease that develops and/or progresses dueto a decrease or deficiency in the activity of FVIII and/or FVIIIa.

Specifically, the present invention relates to a pharmaceuticalcomposition or a dosage regimen used for treating and/or reducing theincidence of a disease that develops and/or progresses due to a decreaseor deficiency in the activity of FVIII and/or FVIIIa, and specificallyrelates to the following:

[1] a method for treating and/or reducing the incidence of a diseasethat develops and/or progresses due to a decrease or deficiency in theactivity of blood coagulation factor VIII and/or activated bloodcoagulation factor VIII (FVIIIa), the method comprising: administeringto a subject a bispecific antibody that recognizes (a) blood coagulationfactor IX and/or activated blood coagulation factor IX and (b) bloodcoagulation factor X and/or activated blood coagulation factor X at aweekly loading dose of 3 mg/kg or 4.5 mg/kg of the antibody for one ormore weeks or at an every-two-week loading dose of 6 mg/kg of theantibody for two or more weeks; and, after the loading doseadministration(s) are complete, administering a maintenance dose of theantibody to the subject one or more times, the maintenance dose being 6mg/kg of the antibody;

[2] the method of [1], wherein the maintenance dose of 6 mg/kg of theantibody is administered to the subject every four weeks or every monthin a single dose or multiple divided doses;

[3] the method of [1] or [2], wherein the antibody is administered atthe weekly loading dose of 3 mg/kg of the antibody for four weeks,followed by the maintenance dose;

[4] the method of [1] or [2], wherein the antibody is administered atthe weekly loading dose of 4.5 mg/kg of the antibody for two weeks,followed by the maintenance dose;

[5] the method of [1] or [2], wherein the antibody is administered atthe every-two-week loading dose of 6 mg/kg of the antibody for fourweeks, followed by the maintenance dose;

[6] the method of any one of [1] to [5], wherein the maintenance dose isadministered in one single dose at 6 mg/kg of the antibody monthly orevery four weeks;

[7] the method of any one of [1] to [5], wherein the maintenance dose isadministered in two single doses of the antibody, each at 3 mg/kg,monthly or every four weeks, wherein one single dose of the maintenancedose at 3 mg/kg of the antibody is administered once every two weeks;

[8] the method of any one of [1] to [5], wherein the maintenance dose isadministered in four single doses each at 1.5 mg/kg of the antibodymonthly or every four weeks, wherein one single dose of the maintenancedose at 1.5 mg/kg of the antibody is administered once every week;

[9] the method of any one of [1] to [8] further comprising, in a case ofno or insufficient effect of treating and/or reducing the incidence ofthe disease by administering the maintenance dose of the antibody,stopping administering the maintenance dose of the antibody and startingadministering an alternative maintenance dose of the antibody to thesubject, the alternative maintenance dose being a weekly dose of 3 mg/kgof the antibody or an every-two-week dose of 6 mg/kg of the antibody;

[10] a method for treating and/or reducing the incidence of a diseasethat develops and/or progresses due to a decrease or deficiency in theactivity of blood coagulation factor VIII and/or activated bloodcoagulation factor VIII (FVIIIa), the method comprising: administeringto a subject a bispecific antibody that recognizes (a) blood coagulationfactor IX and/or activated blood coagulation factor IX and (b) bloodcoagulation factor X and/or activated blood coagulation factor X at aweekly loading dose of 4.5 mg/kg of the antibody for four weeks; andthereafter administering a maintenance dose of the antibody to thesubject one or more times, the maintenance dose being 9 mg/kg of theantibody which is administered every four weeks or every month in two orfour divided doses;

[11] a method for treating and/or reducing the incidence of a diseasethat develops and/or progresses due to a decrease or deficiency in theactivity of blood coagulation factor VIII and/or activated bloodcoagulation factor VIII (FVIIIa), the method comprising: administeringto a subject a bispecific antibody that recognizes (a) blood coagulationfactor IX and/or activated blood coagulation factor IX and (b) bloodcoagulation factor X and/or activated blood coagulation factor X at aweekly loading dose of 6 mg/kg of the antibody for four weeks; andthereafter administering a maintenance dose of the antibody to thesubject one or more times, the maintenance dose being 12 mg/kg of theantibody which is administered every four weeks or every month in two orfour divided doses;

[12] the method of [10] further comprising, in a case of no orinsufficient effect of treating and/or reducing the incidence of thedisease by administering the maintenance dose of the antibody, stoppingadministering the maintenance dose of the antibody and startingadministering an alternative maintenance dose of the antibody to thesubject, the alternative maintenance dose being a weekly dose of 4.5mg/kg of the antibody;

[13] the method of [11] further comprising, in a case of no orinsufficient effect of treating and/or reducing the incidence of thedisease by administering the maintenance dose of the antibody, stoppingadministering the maintenance dose of the antibody and startingadministering an alternative maintenance dose of the antibody to thesubject, the alternative maintenance dose being a weekly dose of 6 mg/kgof the antibody;

[14] the method of any one of [1] to [13], wherein the antibody isemicizumab; and

[15] the method of [14], wherein the disease that develops and/orprogresses due to a decrease or deficiency in the activity of bloodcoagulation factor VIII and/or activated blood coagulation factor VIIIis selected from the group consisting of hemophilia A, acquiredhemophilia A, von Willebrand disease, and hemophilia A with emergence ofan inhibitor against blood coagulation factor VIII and/or activatedblood coagulation factor VIII.

Furthermore, the present invention relates to:

[16] a pharmaceutical composition for use in treating and/or reducingthe incidence of a disease that develops and/or progresses due to adecrease or deficiency in the activity of blood coagulation factor VIIIand/or activated blood coagulation factor VIII (FVIIIa), wherein thecomposition comprises a bispecific antibody that recognizes (a) bloodcoagulation factor IX and/or activated blood coagulation factor IX and(b) blood coagulation factor X and/or activated blood coagulation factorX, wherein the bispecific antibody is administered at a weekly loadingdose of 3 mg/kg or 4.5 mg/kg of the antibody for one or more weeks or atan every-two-week loading dose of 6 mg/kg of the antibody for two ormore weeks and, after the loading dose administration(s) are complete,is administered at a maintenance dose one or more times, the maintenancedose being 6 mg/kg of the antibody;

[17] a pharmaceutical composition for use in treating and/or reducingthe incidence of a disease that develops and/or progresses due to adecrease or deficiency in the activity of blood coagulation factor VIIIand/or activated blood coagulation factor VIII (FVIIIa), wherein thecomposition comprises a bispecific antibody that recognizes (a) bloodcoagulation factor IX and/or activated blood coagulation factor IX and(b) blood coagulation factor X and/or activated blood coagulation factorX, wherein the bispecific antibody is administered at a weekly loadingdose of 4.5 mg/kg of the antibody for four weeks and thereafter isadministered at a maintenance dose one or more times, the maintenancedose being 9 mg/kg of the antibody which is administered every fourweeks or every month in two or four divided doses;

[18] a pharmaceutical composition for use in treating and/or reducingthe incidence of a disease that develops and/or progresses due to adecrease or deficiency in the activity of blood coagulation factor VIIIand/or activated blood coagulation factor VIII (FVIIIa), wherein thecomposition comprises a bispecific antibody that recognizes (a) bloodcoagulation factor IX and/or activated blood coagulation factor IX and(b) blood coagulation factor X and/or activated blood coagulation factorX, wherein the bispecific antibody is administered at a weekly loadingdose of 6 mg/kg of the antibody for four weeks and thereafter isadministered at a maintenance dose one or more times, the maintenancedose being 12 mg/kg of the antibody which is administered every fourweeks or every month in two or four divided doses;

[19] a product comprising (i) a container; (ii) a pharmaceuticalcomposition in the container, wherein the composition comprises abispecific antibody that recognizes (a) blood coagulation factor IXand/or activated blood coagulation factor IX and (b) blood coagulationfactor X and/or activated blood coagulation factor X; and (iii) adocument instructing (a) administration of the bispecific antibody at aweekly loading dose of 3 mg/kg or 4.5 mg/kg of the antibody for one ormore weeks or at an every-two-week loading dose of 6 mg/kg of theantibody for two or more weeks and (b) one or more administration(s) ofa maintenance dose of the bispecific antibody after the loading doseadministration(s) are complete, the maintenance dose being 6 mg/kg ofthe antibody;

[20] a product comprising (i) a container; (ii) a pharmaceuticalcomposition in the container, wherein the composition comprises abispecific antibody that recognizes (a) blood coagulation factor IXand/or activated blood coagulation factor IX and (b) blood coagulationfactor X and/or activated blood coagulation factor X; and (iii) adocument instructing (a) administration of the bispecific antibody at aweekly loading dose of 4.5 mg/kg of the antibody for four weeks and (b)one or more administrations of a maintenance dose of the bispecificantibody after the loading dose administration(s) are complete, themaintenance dose being 9 mg/kg of the antibody which is administeredevery four weeks or every month in two or four divided doses;

[21] a product comprising (i) a container; (ii) a pharmaceuticalcomposition in the container, wherein the composition comprises abispecific antibody that recognizes (a) blood coagulation factor IXand/or activated blood coagulation factor IX and (b) blood coagulationfactor X and/or activated blood coagulation factor X; and (iii) adocument instructing (a) administration of the bispecific antibody at aweekly loading dose of 6 mg/kg of the antibody for four weeks and (b)one or more administrations of a maintenance dose of the bispecificantibody after the loading dose administration(s) are complete, themaintenance dose being 12 mg/kg of the antibody which is administeredevery four weeks or every month in two or four divided doses;

[22] a bispecific antibody for use in treating and/or reducing theincidence of a disease that develops and/or progresses due to a decreaseor deficiency in the activity of blood coagulation factor VIII and/oractivated blood coagulation factor VIII (FVIIIa), wherein the bispecificantibody recognizes (a) blood coagulation factor IX and/or activatedblood coagulation factor IX and (b) blood coagulation factor X and/oractivated blood coagulation factor X and is administered at a weeklyloading dose of 3 mg/kg or 4.5 mg/kg of the antibody for one or moreweeks or at an every-two-week loading dose of 6 mg/kg of the antibodyfor two or more weeks and, after the loading dose administration(s) arecomplete, is administered at a maintenance dose one or more times, themaintenance dose being 6 mg/kg of the antibody;

[23] a bispecific antibody for use in treating and/or reducing theincidence of a disease that develops and/or progresses due to a decreaseor deficiency in the activity of blood coagulation factor VIII and/oractivated blood coagulation factor VIII (FVIIIa), wherein the bispecificantibody recognizes (a) blood coagulation factor IX and/or activatedblood coagulation factor IX and (b) blood coagulation factor X and/oractivated blood coagulation factor X and is administered at a weeklyloading dose of 4.5 mg/kg of the antibody for four weeks and thereafteris administered at a maintenance dose one or more times, the maintenancedose being 9 mg/kg of the antibody which is administered every fourweeks or every month in two or four divided doses;

[24] a bispecific antibody for use in treating and/or reducing theincidence of a disease that develops and/or progresses due to a decreaseor deficiency in the activity of blood coagulation factor VIII and/oractivated blood coagulation factor VIII (FVIIIa), wherein the bispecificantibody recognizes (a) blood coagulation factor IX and/or activatedblood coagulation factor IX and (b) blood coagulation factor X and/oractivated blood coagulation factor X and is administered at a weeklyloading dose of 6 mg/kg of the antibody for four weeks and thereafter isadministered a maintenance dose one or more times, the maintenance dosebeing 12 mg/kg of the antibody which is administered every four weeks orevery month in two or four divided doses;

[25] use of a bispecific antibody in the manufacture of a pharmaceuticalcomposition used for treating and/or reducing the incidence of a diseasethat develops and/or progresses due to a decrease or deficiency in theactivity of blood coagulation factor VIII and/or activated bloodcoagulation factor VIII (FVIIIa), wherein the bispecific antibodyrecognizes (a) blood coagulation factor IX and/or activated bloodcoagulation factor IX and (b) blood coagulation factor X and/oractivated blood coagulation factor X, and is administered at a weeklyloading dose of 3 mg/kg or 4.5 mg/kg of the antibody for one or moreweeks or at an every-two-week loading dose of 6 mg/kg of the antibodyfor two or more weeks and, after the loading dose administration(s) arecomplete, is administered at a maintenance dose one or more times, themaintenance dose being 6 mg/kg of the antibody;

[26] use of a bispecific antibody in the manufacture of a pharmaceuticalcomposition used for treating and/or reducing the incidence of a diseasethat develops and/or progresses due to a decrease or deficiency in theactivity of blood coagulation factor VIII and/or activated bloodcoagulation factor VIII (FVIIIa), wherein the bispecific antibodyrecognizes (a) blood coagulation factor IX and/or activated bloodcoagulation factor IX and (b) blood coagulation factor X and/oractivated blood coagulation factor X, and is administered at a weeklyloading dose of 4.5 mg/kg of the antibody for four weeks and thereafteris administered at a maintenance dose one or more times, the maintenancedose being 9 mg/kg of the antibody which is administered every fourweeks or every month in two or four divided doses; and

[27] use of a bispecific antibody in the manufacture of a pharmaceuticalcomposition used for treating and/or reducing the incidence of a diseasethat develops and/or progresses due to a decrease or deficiency in theactivity of blood coagulation factor VIII and/or activated bloodcoagulation factor VIII (FVIIIa), wherein the bispecific antibodyrecognizes (a) blood coagulation factor IX and/or activated bloodcoagulation factor IX and (b) blood coagulation factor X and/oractivated blood coagulation factor X, and is administered at a weeklyloading dose of 6 mg/kg of the antibody for four weeks and thereafter isadministered at a maintenance dose one or more times, the maintenancedose being 12 mg/kg of the antibody which is administered every fourweeks or every month in two or four divided doses.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 shows the simulated annual bleeding rate over plasma emicizumabconcentrations. X-axis shows plasma emicizumab concentration (microg/mL). Y-axis shows cumulative bleeding count for 52 weeks. Circles andsolid line show the simulated medians plotted at each plasma emicizumabconcentration. Shaded area shows the simulated 5th- to 95th-percentilerange.

FIG. 2 shows the simulated change in plasma emicizumab concentrationover time (weekly dosing). X-axis shows time (week) after firstemicizumab administration. Y-axis shows plasma emicizumab concentration(micro g/mL). Circles and solid line show the simulated medians plottedat each trough sampling time point. Shaded area shows the simulated 5th-to 95th-percentile range. Broken line shows the target exposure level of45 micro g/mL. Once-weekly loading dose of 3 mg/kg for first 4 weeksfollowed by once-weekly maintenance dose of 1.5 mg/kg was applied.

FIG. 3 shows the simulated change in plasma emicizumab concentrationover time (two-weekly dosing). X-axis shows time (week) after firstemicizumab administration. Y-axis shows plasma emicizumab concentration(micro g/mL). Circles and solid line show the simulated medians plottedat each trough sampling time point. Shaded area shows the simulated 5th-to 95th-percentile range. Broken line shows the target exposure level of45 micro g/mL. Once-weekly loading dose of 3 mg/kg for first 4 weeksfollowed by once-every-two-week maintenance dose of 3 mg/kg was applied.

FIG. 4 shows the simulated change in plasma emicizumab concentrationover time (four-weekly dosing). X-axis shows time (week) after firstemicizumab administration. Y-axis shows plasma emicizumab concentration(micro g/mL). Circles and solid line show the simulated medians plottedat each trough sampling time point. Shaded area shows the simulated 5th-to 95th-percentile range. Broken line shows the target exposure level of45 micro g/mL. Once-weekly loading dose of 3 mg/kg for first 4 weeksfollowed by once-every-four-week maintenance dose of 6 mg/kg wasapplied.

FIG. 5 shows the simulated distribution of annual bleeding rate (weeklydosing). X-axis shows cumulative bleeding count for 52 weeks. Y-axisshows proportion of patients having each cumulative bleeding count for52 weeks (%). Bars show the simulated proportions. Once-weekly loadingdose of 3 mg/kg for first 4 weeks followed by once-weekly maintenancedose of 1.5 mg/kg was applied.

FIG. 6 shows the simulated distribution of annual bleeding rate(two-weekly dosing). X-axis shows cumulative bleeding count for 52weeks. Y-axis shows proportion of patients having each cumulativebleeding count for 52 weeks (%). Bars show the simulated proportions.Once-weekly loading dose of 3 mg/kg for first 4 weeks followed byonce-every-two-week maintenance dose of 3 mg/kg was applied.

FIG. 7 shows the simulated distribution of annual bleeding rate(four-weekly dosing). X-axis shows cumulative bleeding count for 52weeks. Y-axis shows proportion of patients having each cumulativebleeding count for 52 weeks (%). Bars show the simulated proportions.Once-weekly loading dose of 3 mg/kg for first 4 weeks followed byonce-every-four-week maintenance dose of 6 mg/kg was applied.

FIG. 8 shows the annualized bleeding rates for study Arms A, B, and C inHAVEN 1 (Example 2). ABR, annualized bleeding rate; BPA, bypassingagent; RR, relative risk.

FIG. 9 shows the intra-participant comparison for treated bleeds inparticipants who received emicizumab prophylaxis (Arm C). Treated bleedsduring the period when a participant received emicizumab prophylaxis arecompared with treated bleeds during the period when the same participanthad received previous prophylactic BPA treatment in 24 weeks prior tostudy entry in HAVEN 1.

FIG. 10 shows the observed trough emicizumab concentrations over timewith once-weekly dosing (once-weekly loading dose of 3 mg/kg for first 4weeks followed by once-weekly maintenance dose of 1.5 mg/kg) in HAVEN 1.SD, standard deviation.

FIG. 11 shows the intra-participant comparison for treated bleeds inparticipants who received emicizumab prophylaxis (Arm A). Treated bleedsduring the period when a participant received emicizumab prophylaxis arecompared with treated bleeds during the period when the same participanthad received previous episodic BPA treatment in 24 weeks prior to studyentry in HAVEN 1.

FIG. 12 shows the individual patient-calculated ABR for treated bleedsin HAVEN 2. The intra-participant comparison included patientspreviously enrolled in the NIS who were enrolled in HAVEN 2 for at least12 weeks. Seven patients received prophylactic treatment with bypassingagents prior to the study, one received episodic treatment withbypassing agents. ABR, annualized bleeding rate; BPA, bypassing agent;NIS, non-interventional study.

FIG. 13 shows the observed and predicted emicizumab concentrations overtime with once-four-weekly dosing in the PK Run-in Part of HAVEN 4(Example 5). Emicizumab was administered subcutaneously at 6 mg/kg onceevery 4 weeks. Black dots and solid lines show the individualobservations. Gray broken line shows the predicted mean. Gray bold solidlines indicate the upper and lower limits of the 95% predictioninterval.

DESCRIPTION OF EMBODIMENTS

A bispecific antigen-binding molecule that recognizes (a) bloodcoagulation factor IX (FIX) and/or activated blood coagulation factor IX(FIXa) and (b) blood coagulation factor X (FX) and/or activated bloodcoagulation factor X (FXa) preferably has an activity of functionallysubstituting for coagulation factor VIII (FVIII).

In the present invention, the phrase “functionally substitute for FVIII”means that (a) FIX and/or FIXa, and (b) FX and/or FXa are recognized,and the activation of FX by FIXa is promoted (FXa generation by FIXa ispromoted). FXa generation-promoting activity can be evaluated using, forexample, a measurement system comprising FIXa, FX, the syntheticsubstrate S-2222 (a synthetic substrate of FXa), and phospholipids. Sucha measurement system shows the correlation between the severity of thedisease and the clinical symptoms in hemophilia A cases (Rosen S,Andersson M, Blomback M et al. Clinical applications of a chromogenicsubstrate method for determination of FVIII activity. Thromb Haemost1985; 54: 811-23).

Such antigen-binding molecules (such as antibodies) recognizing (a) FIXand/or FIXa and (b) FX and/or FXa can be obtained according to methodsdescribed, for example, in WO2005/035756, WO2006/109592, andWO2012/067176. Specifically, based on the sequences of antibodiesagainst FIX and/or FIXa and antibodies against FX and/or FXa, antibodiescan be generated using genetic recombination techniques known to thoseskilled in the art. Polynucleotide(s) encoding an antibody can beconstructed based on the sequences of the antibodies against FIX and/orFIXa and antibodies against FX and/or FXa, and this can be inserted intoan expression vector and subsequently expressed in appropriate hostcells (see for example, Co, M. S. et al., J. Immunol. (1994) 152,2968-2976; Better, M. and Horwitz, A. H., Methods Enzymol. (1989) 178,476-496; Pluckthun, A. and Skerra, A., Methods Enzymol. (1989) 178,497-515; Lamoyi, E., Methods Enzymol. (1986) 121, 652-663; Rousseaux, J.et al., Methods Enzymol. (1986) 121, 663-669; and Bird, R. E. andWalker, B. W., Trends Biotechnol.

In the present invention, the phrases “functionally substitute forFVIII” and “functionally substitute for FVIIIa” are usedinterchangeably.

Such bispecific antigen-binding molecules can be isolated from insidehost cells or from outside the cells (such as from the medium), and canbe purified as substantially pure and homogeneous antibodies. Isolationand purification of antibodies can be carried out using methodsgenerally used for isolating and purifying antibodies. The methods arenot limited and, for example, antibodies can be isolated and purified byappropriately selecting and combining column chromatography columns,filters, ultrafiltration, salting-out, solvent precipitation, solventextraction, distillation, immunoprecipitation, SDS-polyacrylamide gelelectrophoresis, isoelectric focusing, dialysis, recrystallization, andsuch.

The bispecific antigen-binding molecules of the present inventioninclude the antibodies described, for example, in WO2005/035756,WO2006/109592, and WO2012/067176.

A bispecific antigen-binding molecule comprises a first antigen-bindingsite and a second antigen-binding site which can specifically bind to atleast two different types of antigens. While the first antigen-bindingsite and the second antigen-binding site of the bispecificantigen-binding molecule of the present invention are not particularlylimited as long as they have an activity to bind to (a) FIX and/or FIXa,and (b) FX and/or FXa, respectively, examples include sites necessaryfor binding with antigens, such as antibodies, scaffold molecules(antibody-like molecules), and peptides, and fragments containing suchsites. A scaffold molecule is a molecule that exhibits a function bybinding to a target molecule, and any polypeptide may be used as long asit is a conformationally stable polypeptide that can bind to at leastone target antigen. Examples of such polypeptides include antibodyvariable regions, fibronectin (WO 2002/032925), protein A domain (WO1995/001937), LDL receptor A domain (WO 2004/044011, WO 2005/040229),ankyrin (WO 2002/020565), as well as the molecules described in Nygrenet al. (Current Opinion in Structural Biology, 7: 463-469 (1997); andJournal of Immunol Methods, 290: 3-28 (2004)), Binz et al. (NatureBiotech 23: 1257-1266 (2005)), and Hosse et al. (Protein Science 15:14-27(2006)). Furthermore, as described in Curr Opin Mol Ther. 2010August; 12(4): 487-95 and Drugs. 2008; 68(7): 901-12, peptide moleculesthat can bind to the target antigens can also be used.

Bispecific antigen-binding molecules can be produced using, for example,genetic recombination techniques (see, for example, Borrebaeck C A K andLarrick J W, THERAPEUTIC MONOCLONAL ANTIBODIES, Published in the UnitedKingdom by MACMILLAN PUBLISHERS LTD, 1990). Recombinant antibodies canbe obtained by cloning DNAs encoding the antibodies from hybridomas orantibody-producing cells, such as sensitized lymphocytes that produceantibodies, inserting them into suitable vectors, and then introducingthem into hosts (host cells) to produce the antibodies.

Furthermore, bispecific antigen-binding molecules may be wholeantibodies, and may also be antibody fragments and low-molecular-weightantibodies, and modified antibodies.

For example, antibody fragments and low-molecular-weight antibodiesinclude diabodies (Dbs), linear antibodies, and single chain antibody(hereinafter, also denoted as scFv) molecules. Herein, an “Fv” fragmentis a smallest antibody fragment and comprises a full antigen recognitionsite and binding site.

Bispecific antibodies include human antibodies, mouse antibodies, ratantibodies, and such, and their origins are not limited. They may alsobe genetically modified antibodies, such as chimeric antibodies andhumanized antibodies.

Methods for obtaining human antibodies are already known. For example, ahuman antibody of interest can be obtained by immunizing a transgenicanimal carrying the entire repertoire of human antibody genes with anantigen of interest (see International Publication No. WO 93/12227, WO92/03918, WO 94/02602, WO 94/25585, WO 96/34096, and WO 96/33735).

Genetically modified antibodies can also be produced using knownmethods. Specifically, for example, a chimeric antibody is an antibodythat comprises H chain and L chain variable regions of an immunizedanimal antibody, and H chain and L chain constant regions of a humanantibody. Chimeric antibodies can be obtained by linking DNAs encodingthe variable regions of an antibody derived from an immunized animalwith DNAs encoding the constant regions of a human antibody, insertingthis into an expression vector, and then introducing this into hostcells to produce the antibodies.

A humanized antibody is a modified antibody which is also often referredto as a reshaped human antibody. A humanized antibody is constructed bytransferring the CDRs of an antibody derived from an immunized animal tothe complementarity determining regions of a human antibody. Generalgenetic recombination techniques for producing them are also known (seeEuropean Patent Application Publication No. EP 239400; InternationalPublication No. WO 96/02576; Sato K et al., Cancer Research 1993, 53:851-856; International Publication No. WO 99/51743).

More specifically, the bispecific antigen-binding molecule of thepresent invention is a bispecific antibody in which a first polypeptideand a third polypeptide are associated and a second polypeptide and afourth polypeptide are associated, and is preferably emicizumab (ACE910,RO5534262) described below:

(a) a bispecific antibody comprising a first polypeptide which is an Hchain containing an H chain variable region containing CDR 1, 2, and 3amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively; a secondpolypeptide which is an H chain containing an H chain variable regioncontaining CDR 1, 2, and 3 amino acid sequences of SEQ ID NOs: 6, 7, and8, respectively; and a third and fourth polypeptide which are a commonlyshared L chain containing an L chain variable region containing CDR 1,2, and 3 amino acid sequences of SEQ ID NOs: 11, 12, and 13,respectively;

(b) a bispecific antibody comprising a first polypeptide which is an Hchain containing an H chain variable region amino acid sequence of SEQID NO: 4;

a second polypeptide which is an H chain containing an H chain variableregion amino acid sequence of SEQ ID NO: 9; and a third and fourthpolypeptide which are a commonly shared L chain containing an L chainvariable region amino acid sequence of SEQ ID NO: 14; or

(c) a bispecific antibody comprising a first polypeptide which is an Hchain containing the amino acid sequence of SEQ ID NO: 5; a secondpolypeptide which is an H chain containing the amino acid sequence ofSEQ ID NO: 10; and a third and fourth polypeptide which are a commonlyshared L chain containing the amino acid sequence of SEQ ID NO: 15(Q499-z121/J327-z119/L404-k).

Pharmaceutical compositions of the present invention which are used fortherapeutic or preventive purposes can be prepared by mixing atherapeutic agent, if necessary, with suitable pharmaceuticallyacceptable carriers, vehicles, and such and made into a freeze-dryformulation or a solution formulation.

A “therapeutic agent” herein refers to the bispecific antigen-bindingmolecules of the present invention.

Examples of suitable pharmaceutically acceptable carriers and vehiclesinclude sterilized water, physiological saline, stabilizers, excipients,antioxidants (such as ascorbic acid), buffers (such as phosphate,citrate, histidine, and other organic acids), antiseptics, surfactants(such as PEG and Tween), chelating agents (such as EDTA), and binders.They may also contain other low-molecular-weight polypeptides, proteinssuch as serum albumin, gelatin, and immunoglobulins, amino acids such asglycine, glutamine, asparagine, glutamic acid, aspartic acid,methionine, arginine, and lysine, sugars and carbohydrates such aspolysaccharides and monosaccharides, and sugar alcohols such as mannitoland sorbitol. When preparing an aqueous solution for injection, forexample, physiological saline and isotonic solutions containing glucoseand other adjuvants such as D-sorbitol, D-mannose, D-mannitol, andsodium chloride may be used, and appropriate solubilizers such asalcohol (for example, ethanol), polyalcohols (such as propylene glycoland PEG), and nonionic surfactants (such as polysorbate 80, polysorbate20, poloxamer 188, and HCO-50) may be used in combination. By mixinghyaluronidase into the formulation, a larger fluid volume can beadministered subcutaneously (Expert Opin Drug Deliv. 2007 July; 4(4):427-40). Further, the pharmaceutical compositions of the presentinvention may be preliminarily loaded in a syringe. Meanwhile, thesolution formulation can be prepared according to the method describedin WO 2011/090088.

If necessary, the antigen-binding molecules of the present invention canbe encapsulated in microcapsules (e.g., those made ofhydroxymethylcellulose, gelatin, and poly(methylmetacrylate)), orprepared as colloidal drug delivery systems (e.g., liposomes, albuminmicrospheres, microemulsion, nanoparticles, and nanocapsules) (see, forexample, “Remington's Pharmaceutical Science 16th edition”, Oslo Ed.(1980)). Methods for preparing the pharmaceutical agents ascontrolled-release pharmaceutical agents are also well known, and suchmethods may be applied to the antigen-binding molecules of the presentinvention (Langer et al., J. Biomed. Mater. Res. 15: 267-277 (1981);Langer, Chemtech. 12: 98-105 (1982); U.S. Pat. No. 3,773,919; EuropeanPatent Application Publication No. EP 58,481; Sidman et al., Biopolymers22: 547-556 (1983); EP 133,988).

A preferable liquid formulation is as follows.

20 mg/ml to 180 mg/ml emicizumab,

0.2 mg/ml to 1 mg/ml of poloxamer 188,

10 mM to 40 mM of histidine-aspartic acid buffer,

100 mM to 300 mM of arginine, at a pH of about 4.5 to 6.5.

The pharmaceutical compositions of the present invention can beadministered to a patient via any appropriate route, for example,intravenously by bolus injection or continuous infusion for a givenperiod, intramuscularly, intraperitoneally, intracerebrospinally,transdermally, subcutaneously, intraarticularly, sublingually,intrasynovially, orally, by inhalation, locally, or externally.Intravenous administration or subcutaneous administration is preferred.

The term “4 weeks” or “a month” as used herein are used interchangeablyand the term “every 4 weeks”, “4-weekly”, “every month”, or “monthly” asused herein are used interchangeably.

The term “every 2 weeks”, “2-weekly”, or “bi-weekly” as used herein areused interchangeably.

A “maintenance” dose herein refers to one or more doses of a therapeuticagent administered to the patient over a treatment period. Differentmaintenance doses and different administration intervals can becombined.

In one aspect, the maintenance dose is between 0.3 mg/kg to 24 mg/kg ofthe antibody.

In one aspect, the administration interval is between one week to 24weeks or 6 months.

In one aspect, the maintenance dose is 6 mg/kg of the antibody. Themaintenance dose of 6 mg/kg refers to, for example, administering total6 mg/kg of the antibody during 4 weeks or every month in a single doseor multiple divided doses.

In certain embodiment, the maintenance dose is 6 mg/kg of the antibodyand this is administered in a single dose and the administrationinterval is 4 weeks (every month). In this case one single dose isadministered during a month or 4 weeks.

In another embodiment, the maintenance dose is 6 mg/kg of the antibodyand this is administered in two divided doses each containing 3 mg/kg ofthe antibody and the administration interval is two weeks (every 2weeks). In this case two doses are administered during a month or 4weeks.

In another embodiment, the maintenance dose is 6 mg/kg of the antibodyand this is administered in four divided doses each containing 1.5 mg/kgof the antibody and the administration interval is one week (everyweek). In this case four doses are administered during a month or 4weeks.

In certain embodiment, the maintenance dose is 6 mg/kg of the antibodyin a single dose and the administration interval is 4 weeks (everymonth) and in this case one dose is administered during a month or 4weeks.

In another embodiment, the maintenance dose is 3 mg/kg of the antibodyin a single dose and the administration interval is two weeks (every 2weeks) and in this case two doses are administered during a month or 4weeks.

In another embodiment, the maintenance dose is 1.5 mg/kg of the antibodyin a single dose and the administration interval is one week (everyweek) and in this case four doses are administered during a month or 4weeks.

In another aspect, the maintenance dose is 9 mg/kg of the antibody. Themaintenance dose of 9 mg/kg refers to, for example, administering total9 mg/kg of the antibody during 4 weeks or every month in a single doseor multiple divided doses. This can be applicable for pediatric patientsor such special population of patients likely to exhibit lower exposure.

In certain embodiment, the maintenance dose is 9 mg/kg of the antibodyand this is administered in two divided doses each containing 4.5 mg/kgof the antibody and the administration interval is two weeks (every 2weeks). In this case two doses are administered during a month or 4weeks.

In another embodiment, the maintenance dose is 9 mg/kg of the antibodyand this is administered in four divided doses each containing 2.25mg/kg of the antibody and the administration interval is one week (everyweek). In this case four doses are administered during a month or 4weeks.

In certain another embodiment, the maintenance dose is 4.5 mg/kg of theantibody in a single dose and the administration interval is two weeks(every 2 weeks) and in this case two doses are administered during amonth or 4 weeks.

In another embodiment, the maintenance dose is 2.25 mg/kg of theantibody in a single dose and the administration interval is one week(every week) and in this case four doses are administered during a monthor 4 weeks.

In another aspect, the maintenance dose is 12 mg/kg of the antibody. Themaintenance dose of 12 mg/kg refers to, for example, administering total12 mg/kg of the antibody during 4 weeks or every month in a single doseor multiple divided doses. This can be applicable for pediatric patientsor such special population of patients likely to exhibit lower exposure.

In certain embodiment, the maintenance dose is 12 mg/kg of the antibodyand this is administered in two divided doses each containing 6 mg/kg ofthe antibody and the administration interval is two weeks (every 2weeks). In this case two doses are administered during a month or 4weeks.

In another embodiment, the maintenance dose is 12 mg/kg of the antibodyand this is administered in four divided doses each containing 3 mg/kgof the antibody and the administration interval is one week (everyweek). In this case four doses are administered during a month or 4weeks.

In certain embodiment, the maintenance dose is 6 mg/kg of the antibodyin a single dose and the administration interval is two weeks (every 2weeks) and in this case two doses are administered during a month or 4weeks.

In another embodiment, the maintenance dose is 3 mg/kg of the antibodyin a single dose and the administration interval is one week (everyweek) and in this case four doses are administered during a month or 4weeks.

In another aspect, a different or alternative maintenance dose andadministration interval can be applicable.

In certain embodiments, a different or alternative maintenance dose andadministration interval can be applicable after the above-mentionedinitial maintenance doses and administration intervals. Morespecifically, one may modify the above-mentioned every-4-week 6 mg/kgantibody maintenance dosing regimen, every-4-week 9 mg/kg antibodymaintenance dosing regimen, and/or every-4-week 12 mg/kg antibodymaintenance dosing regimen to apply a different, alternative, ormodified maintenance dose and administration interval. For example,after carrying out the administration in any of the above-mentionedevery-4-week 6 mg/kg antibody maintenance dosing regimen, every-4-week 9mg/kg antibody maintenance dosing regimen, and every-4-weeks 12 mg/kgantibody maintenance dosing regimen, one may assess whether theadministration of the maintenance dose was sufficient to treat thesubject. If the administration of the maintenance dose is turned out tobe insufficient or to cause no or insufficient treatment effect and/orpreventive effect, then, one may stop administering the maintenance doseof the antibody and start administering a modified maintenance dose. Theeffect of the administration of the maintenance dose may be assessed atleast 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 16, 20, 24, 36, 48, 60, ormore weeks after the start of the administration of the maintenancedose. There is no particular limitation on the number of times that onecan change the maintenance dose. The changes of the maintenance dose maybe made several times, e.g., once to four times. In other words, one toseveral, e.g. one to five, different maintenance doses may be applied ina sequential manner, such as (0) administering a maintenance dose, (1)stopping administering the maintenance dose and starting administering afirst modified maintenance dose, (2) stopping administering the firstmodified maintenance dose and starting administering a second modifiedmaintenance dose, (3) stopping administering the second modifiedmaintenance dose and starting administering a third modified maintenancedose, (4) stopping administering the third modified maintenance dose andstarting administering a fourth modified maintenance dose.

In some embodiments, the modified maintenance dose may be applied fromthe beginning, without using the above-mentioned every-4-week 6 mg/kgantibody maintenance dosing regimen, every-4-week 9 mg/kg antibodymaintenance dosing regimen, and/or every-4-week 12 mg/kg antibodymaintenance dosing regimen.

In certain embodiment, the modified maintenance dose is 6 mg/kg of theantibody. The modified maintenance dose of 6 mg/kg refers to, forexample, administering total 6 mg/kg of the antibody during 2 weeks orevery 2 weeks as a single dose or multiple divided doses.

In certain embodiment, the modified maintenance dose is 6 mg/kg of theantibody and this is administered in a single dose and the modifiedadministration interval is 2 weeks (every 2 weeks). In this case onesingle dose is administered during 2 weeks.

In another embodiment, the modified maintenance dose is 6 mg/kg of theantibody and this is administered in two divided doses each containing 3mg/kg of the antibody and the modified administration interval is oneweek (every week). In this case two doses are administered during 2weeks.

In certain embodiment, the modified maintenance dose is 6 mg/kg of theantibody in a single dose and the modified administration interval istwo weeks (every 2 weeks) and in this case two doses are administeredduring a month or 4 weeks, or in other words one single dose isadministered during 2 weeks.

In another embodiment, the modified maintenance dose is 3 mg/kg of theantibody in a single dose and the modified administration interval isone week (every week) and in this case two doses are administered during2 weeks.

In certain embodiment, the modified maintenance dose is 9 mg/kg of theantibody. The modified maintenance dose of 9 mg/kg refers to, forexample, administering total 9 mg/kg of the antibody during 2 weeks orevery 2 weeks as a single dose or multiple divided doses. This can beapplicable for pediatric patients or such special population of patientslikely to exhibit lower exposure.

In another embodiment, the modified maintenance dose is 9 mg/kg of theantibody and this is administered in two divided doses each containing4.5 mg/kg of the antibody and the modified administration interval isone week (every week). In this case two doses are administered during 2weeks.

In another embodiment, the modified maintenance dose is 4.5 mg/kg of theantibody in a single dose and the modified administration interval isone week (every week) and in this case four doses are administeredduring a month or 4 weeks, or in other words two doses are administeredduring 2 weeks.

In certain embodiment, the modified maintenance dose is 12 mg/kg of theantibody. The modified maintenance dose of 12 mg/kg refers to, forexample, administering total 12 mg/kg of the antibody during 2 weeks orevery 2 weeks as a single dose or multiple divided doses. This can beapplicable for pediatric patients or such special population of patientslikely to exhibit lower exposure.

In another embodiment, the modified maintenance dose is 12 mg/kg of theantibody and this is administered in two divided doses each containing 6mg/kg of the antibody and the modified administration interval is oneweek (every week). In this case two doses are administered during 2weeks.

In another embodiment with referring to each divided dose above as themodified maintenance dose, the modified maintenance dose is 6 mg/kg ofthe antibody in a single dose and the modified administration intervalis one week (every week) and in this case four doses are administeredduring a month or 4 weeks, or in other words two doses are administeredduring 2 weeks.

A “loading” dose herein generally comprises an initial dose of atherapeutic agent administered to a patient, and is followed by one ormore maintenance dose(s) thereof. In one aspect, the loading dose refersto the amount given at each individual administration and theadministration can be carried out between zero time to 24 times,preferably at least once, at least twice, at least three times, at leastfour times, or more and preferably twice or four times. Usually, theloading doses are administered at spaced treatment intervals, such asbetween one week to 4 weeks apart and preferably approximately everyweek, approximately every 2 weeks, approximately every 3 weeks, orapproximately every 4 weeks (every month). In one aspect, the loadingdose is between 0.3 mg/kg to 30 mg/kg and preferably 3 mg/kg, 4.5 mg/kg,or 6 mg/kg of the antibody. The loading doses were intended to achievethe steady-state therapeutic plasma concentration as early as possible.

In certain embodiment, the loading dose is 3 mg/kg and theadministration interval is one week (every week) and the administrationis repeated four times.

In another embodiment, the loading dose is 4.5 mg/kg and theadministration interval is one week (every week) and the administrationis repeated twice or four times.

In another embodiment, the loading dose is 6 mg/kg and theadministration interval is one week (every week) and the administrationis repeated four times.

In another embodiment, the loading dose is 6 mg/kg and theadministration interval is two weeks (every 2 weeks) and theadministration is repeated twice.

The number of times the maintenance dose is administered is notparticularly limited, and the number is for example at least once, atleast twice, at least three times, at least four times, at least fivetimes, at least six times, at least seven times, at least eight times,at least nine times, at least ten times, at least 15 times, at least 20times, at least 25 times, at least 35 times, at least 40 times, at least50 times, at least 60 times, at least 70 times, at least 80 times, atleast 90 times, at least 100 times, at least 500 times, at least 1000times, at least 10000 times, or more.

“Administration interval” (an interval between individualadministrations) indicates the interval between administration of then^(th) loading dose (n is an integer of 1 or greater) and administrationof the (n+1)^(th) loading dose, and the interval between administrationof the n^(th) maintenance dose (n is an integer of 1 or greater) andadministration of the (n+1)^(th) maintenance dose.

In certain embodiment, the antibody is administered as follows.

Regimen A: administration at the loading dose of 3 mg/kg of the antibodyonce every week for four weeks followed by administration at themaintenance dose of 1.5 mg/kg of the antibody once every week (weekly).

Regimen B: administration at the loading dose of 3 mg/kg of the antibodyonce every week for four weeks followed by administration at themaintenance dose of 1.5 mg/kg of the antibody once every week (weekly)followed by administration at the modified maintenance dose of 3 mg/kgof the antibody once every week.

Regimen C: administration at the loading dose of 3 mg/kg of the antibodyonce every week for four weeks followed by administration at themaintenance dose of 1.5 mg/kg of the antibody once every week (weekly)followed by administration at the modified maintenance dose of 6 mg/kgof the antibody once every two weeks.

Regimen D: administration at the loading dose of 3 mg/kg of the antibodyonce every week for four weeks followed by administration at themaintenance dose of 3 mg/kg of the antibody once every two weeks.

Regimen E: administration at the loading dose of 3 mg/kg of the antibodyonce every week for four weeks followed by administration at themaintenance dose of 3 mg/kg of the antibody once every two weeksfollowed by administration at the modified maintenance dose of 3 mg/kgof the antibody once every week.

Regimen F: administration at the loading dose of 3 mg/kg of the antibodyonce every week for four weeks followed by administration at themaintenance dose of 3 mg/kg of the antibody once every two weeksfollowed by administration at the modified maintenance dose of 6 mg/kgof the antibody once every two weeks.

Regimen G: administration at the loading dose of 3 mg/kg of the antibodyonce every week for four weeks followed by administration at themaintenance dose of 6 mg/kg of the antibody once every four weeks (everymonth).

Regimen H: administration at the loading dose of 3 mg/kg of the antibodyonce every week for four weeks followed by administration at themaintenance dose of 6 mg/kg of the antibody once every four weeks (everymonth) followed by administration at the modified maintenance dose of 3mg/kg of the antibody once every week.

Regimen I: administration at the loading dose of 3 mg/kg of the antibodyonce every week for four weeks followed by administration at themaintenance dose of 6 mg/kg of the antibody once every four weeks (everymonth) followed by administration at the modified maintenance dose of 6mg/kg of the antibody once every two weeks.

Regimen J: administration at the loading dose of 4.5 mg/kg of theantibody once every week for two weeks followed by administration at themaintenance dose of 1.5 mg/kg of the antibody once every week (weekly).

Regimen K: administration at the loading dose of 4.5 mg/kg of theantibody once every week for two weeks followed by administration at themaintenance dose of 1.5 mg/kg of the antibody once every week (weekly)followed by administration at the modified maintenance dose of 3 mg/kgof the antibody once every week.

Regimen L: administration at the loading dose of 4.5 mg/kg of theantibody once every week for two weeks followed by administration at themaintenance dose of 1.5 mg/kg of the antibody once every week (weekly)followed by administration at the modified maintenance dose of 6 mg/kgof the antibody once every two weeks.

Regimen M: administration at the loading dose of 4.5 mg/kg of theantibody once every week for two weeks followed by administration at themaintenance dose of 3 mg/kg of the antibody once every two weeks.

Regimen N: administration at the loading dose of 4.5 mg/kg of theantibody once every week for two weeks followed by administration at themaintenance dose of 3 mg/kg of the antibody once every two weeksfollowed by administration at the modified maintenance dose of 3 mg/kgof the antibody once every week.

Regimen O: administration at the loading dose of 4.5 mg/kg of theantibody once every week for two weeks followed by administration at themaintenance dose of 3 mg/kg of the antibody once every two weeksfollowed by administration at the modified maintenance dose of 6 mg/kgof the antibody once every two weeks.

Regimen P: administration at the loading dose of 4.5 mg/kg of theantibody once every week for two weeks followed by administration at themaintenance dose of 6 mg/kg of the antibody once every four weeks (everymonth).

Regimen Q: administration at the loading dose of 4.5 mg/kg of theantibody once every week for two weeks followed by administration at themaintenance dose of 6 mg/kg of the antibody once every four weeks (everymonth) followed by administration at the modified maintenance dose of 3mg/kg of the antibody once every week.

Regimen R: administration at the loading dose of 4.5 mg/kg of theantibody once every week for two weeks followed by administration at themaintenance dose of 6 mg/kg of the antibody once every four weeks (everymonth) followed by administration at the modified maintenance dose of 6mg/kg of the antibody once every two weeks.

Regimen S: administration at the loading dose of 6 mg/kg of the antibodyonce every two weeks for four weeks followed by administration at themaintenance dose of 1.5 mg/kg of the antibody once every week (weekly).

Regimen T: administration at the loading dose of 6 mg/kg of the antibodyonce every two weeks for four weeks followed by administration at themaintenance dose of 1.5 mg/kg of the antibody once every week (weekly)followed by administration at the modified maintenance dose of 3 mg/kgof the antibody once every week.

Regimen U: administration at the loading dose of 6 mg/kg of the antibodyonce every two weeks for four weeks followed by administration at themaintenance dose of 1.5 mg/kg of the antibody once every week (weekly)followed by administration at the modified maintenance dose of 6 mg/kgof the antibody once every two weeks.

Regimen V: administration at the loading dose of 6 mg/kg of the antibodyonce every two weeks for four weeks followed by administration at themaintenance dose of 3 mg/kg of the antibody once every two weeks.

Regimen W: administration at the loading dose of 6 mg/kg of the antibodyonce every two weeks for four weeks followed by administration at themaintenance dose of 3 mg/kg of the antibody once every two weeksfollowed by administration at the modified maintenance dose of 3 mg/kgof the antibody once every week.

Regimen X: administration at the loading dose of 6 mg/kg of the antibodyonce every two weeks for four weeks followed by administration at themaintenance dose of 3 mg/kg of the antibody once every two weeksfollowed by administration at the modified maintenance dose of 6 mg/kgof the antibody once every two weeks.

Regimen Y: administration at the loading dose of 6 mg/kg of the antibodyonce every two weeks for four weeks followed by administration at themaintenance dose of 6 mg/kg of the antibody once every four weeks (everymonth).

Regimen Z: administration at the loading dose of 6 mg/kg of the antibodyonce every two weeks for four weeks followed by administration at themaintenance dose of 6 mg/kg of the antibody once every four weeks (everymonth) followed by administration at the modified maintenance dose of 3mg/kg of the antibody once every week.

Regimen AA: administration at the loading dose of 6 mg/kg of theantibody once every two weeks for four weeks followed by administrationat the maintenance dose of 6 mg/kg of the antibody once every four weeks(every month) followed by administration at the modified maintenancedose of 6 mg/kg of the antibody once every two weeks.

Regimen AB: administration at the loading dose of 4.5 mg/kg of theantibody once every week (weekly) for four weeks followed byadministration at the maintenance dose of 2.25 mg/kg of the antibodyonce every week (weekly).

Regimen AC: administration at the loading dose of 4.5 mg/kg of theantibody once every week (weekly) for four weeks followed byadministration at the maintenance dose of 2.25 mg/kg of the antibodyonce every week (weekly) followed by administration at the modifiedmaintenance dose of 4.5 mg/kg of the antibody once every week (weekly).

Regimen AD: administration at the loading dose of 4.5 mg/kg of theantibody once every week (weekly) for four weeks followed byadministration at the maintenance dose of 4.5 mg/kg of the antibody onceevery two weeks.

Regimen AE: administration at the loading dose of 4.5 mg/kg of theantibody once every week (weekly) for four weeks followed byadministration at the maintenance dose of 4.5 mg/kg of the antibody onceevery two weeks followed by administration at the modified maintenancedose of 4.5 mg/kg of the antibody once every week (weekly).

Regimen AF: administration at the loading dose of 6 mg/kg of theantibody once every week (weekly) for four weeks followed byadministration at the maintenance dose of 3 mg/kg of the antibody onceevery week (weekly).

Regimen AG: administration at the loading dose of 6 mg/kg of theantibody once every week (weekly) for four weeks followed byadministration at the maintenance dose of 3 mg/kg of the antibody onceevery week (weekly) followed by administration at the modifiedmaintenance dose of 6 mg/kg of the antibody once every week (weekly).

Regimen AH: administration at the loading dose of 6 mg/kg of theantibody once every week (weekly) for four weeks followed byadministration at the maintenance dose of 6 mg/kg of the antibody onceevery two weeks.

Regimen AI: administration at the loading dose of 6 mg/kg of theantibody once every week (weekly) for four weeks followed byadministration at the maintenance dose of 6 mg/kg of the antibody onceevery two weeks followed by administration at the modified maintenancedose of 6 mg/kg of the antibody once every week (weekly).

Regimen AJ: administration at the loading dose of 4.5 mg/kg of theantibody once every week (weekly) for four weeks followed byadministration at the maintenance dose of 2.25 mg/kg of the antibodyonce every week (weekly) followed by administration at the modifiedmaintenance dose of 9 mg/kg of the antibody once every two weeks.

Regimen AK: administration at the loading dose of 4.5 mg/kg of theantibody once every week (weekly) for four weeks followed byadministration at the maintenance dose of 4.5 mg/kg of the antibody onceevery two weeks followed by administration at the modified maintenancedose of 9 mg/kg of the antibody once every two weeks.

Regimen AL: administration at the loading dose of 4.5 mg/kg of theantibody once every week (weekly) for four weeks followed byadministration at the maintenance dose of 9 mg/kg of the antibody onceevery four weeks (every month).

Regimen AM: administration at the loading dose of 4.5 mg/kg of theantibody once every week (weekly) for four weeks followed byadministration at the maintenance dose of 9 mg/kg of the antibody onceevery four weeks (every month) followed by administration at themodified maintenance dose of 4.5 mg/kg of the antibody once every week(weekly).

Regimen AN: administration at the loading dose of 4.5 mg/kg of theantibody once every week (weekly) for four weeks followed byadministration at the maintenance dose of 9 mg/kg of the antibody onceevery four weeks (every month) followed by administration at themodified maintenance dose of 9 mg/kg of the antibody once every twoweeks.

Regimen AO: administration at the loading dose of 6.75 mg/kg of theantibody once every week (weekly) for two weeks followed byadministration at the maintenance dose of 2.25 mg/kg of the antibodyonce every week (weekly).

Regimen AP: administration at the loading dose of 6.75 mg/kg of theantibody once every week (weekly) for two weeks followed byadministration at the maintenance dose of 2.25 mg/kg of the antibodyonce every week (weekly) followed by administration at the modifiedmaintenance dose of 4.5 mg/kg of the antibody once every week (weekly).

Regimen AQ: administration at the loading dose of 6.75 mg/kg of theantibody once every week (weekly) for two weeks followed byadministration at the maintenance dose of 2.25 mg/kg of the antibodyonce every week (weekly) followed by administration at the modifiedmaintenance dose of 9 mg/kg of the antibody once every two weeks.

Regimen AR: administration at the loading dose of 6.75 mg/kg of theantibody once every week (weekly) for two weeks followed byadministration at the maintenance dose of 4.5 mg/kg of the antibody onceevery two weeks.

Regimen AS: administration at the loading dose of 6.75 mg/kg of theantibody once every week (weekly) for two weeks followed byadministration at the maintenance dose of 4.5 mg/kg of the antibody onceevery two weeks followed by administration at the modified maintenancedose of 4.5 mg/kg of the antibody once every week (weekly).

Regimen AT: administration at the loading dose of 6.75 mg/kg of theantibody once every week (weekly) for two weeks followed byadministration at the maintenance dose of 4.5 mg/kg of the antibody onceevery two weeks followed by administration at the modified maintenancedose of 9 mg/kg of the antibody once every two weeks.

Regimen AU: administration at the loading dose of 6.75 mg/kg of theantibody once every week (weekly) for two weeks followed byadministration at the maintenance dose of 9 mg/kg of the antibody onceevery four weeks (every month).

Regimen AV: administration at the loading dose of 6.75 mg/kg of theantibody once every week (weekly) for two weeks followed byadministration at the maintenance dose of 9 mg/kg of the antibody onceevery four weeks (every month) followed by administration at themodified maintenance dose of 4.5 mg/kg of the antibody once every week(weekly).

Regimen AW: administration at the loading dose of 6.75 mg/kg of theantibody once every week (weekly) for two weeks followed byadministration at the maintenance dose of 9 mg/kg of the antibody onceevery four weeks (every month) followed by administration at themodified maintenance dose of 9 mg/kg of the antibody once every twoweeks.

Regimen AX: administration at the loading dose of 9 mg/kg of theantibody once every two weeks for four weeks followed by administrationat the maintenance dose of 2.25 mg/kg of the antibody once every week(weekly).

Regimen AY: administration at the loading dose of 9 mg/kg of theantibody once every two weeks for four weeks followed by administrationat the maintenance dose of 2.25 mg/kg of the antibody once every week(weekly) followed by administration at the modified maintenance dose of4.5 mg/kg of the antibody once every week (weekly).

Regimen AZ: administration at the loading dose of 9 mg/kg of theantibody once every two weeks for four weeks followed by administrationat the maintenance dose of 2.25 mg/kg of the antibody once every week(weekly) followed by administration at the modified maintenance dose of9 mg/kg of the antibody once every two weeks.

Regimen BA: administration at the loading dose of 9 mg/kg of theantibody once every two weeks for four weeks followed by administrationat the maintenance dose of 4.5 mg/kg of the antibody once every twoweeks.

Regimen BB: administration at the loading dose of 9 mg/kg of theantibody once every two weeks for four weeks followed by administrationat the maintenance dose of 4.5 mg/kg of the antibody once every twoweeks followed by administration at the modified maintenance dose of 4.5mg/kg of the antibody once every week (weekly).

Regimen BC: administration at the loading dose of 9 mg/kg of theantibody once every two weeks for four weeks followed by administrationat the maintenance dose of 4.5 mg/kg of the antibody once every twoweeks followed by administration at the modified maintenance dose of 9mg/kg of the antibody once every two weeks.

Regimen BD: administration at the loading dose of 9 mg/kg of theantibody once every two weeks for four weeks followed by administrationat the maintenance dose of 9 mg/kg of the antibody once every four weeks(every month).

Regimen BE: administration at the loading dose of 9 mg/kg of theantibody once every two weeks for four weeks followed by administrationat the maintenance dose of 9 mg/kg of the antibody once every four weeks(every month) followed by administration at the modified maintenancedose of 4.5 mg/kg of the antibody once every week (weekly).

Regimen BF: administration at the loading dose of 9 mg/kg of theantibody once every two weeks for four weeks followed by administrationat the maintenance dose of 9 mg/kg of the antibody once every four weeks(every month) followed by administration at the modified maintenancedose of 9 mg/kg of the antibody once every two weeks.

Regimen BG: administration at the loading dose of 6 mg/kg of theantibody once every week (weekly) for four weeks followed byadministration at the maintenance dose of 3 mg/kg of the antibody onceevery week (weekly) followed by administration at the modifiedmaintenance dose of 12 mg/kg of the antibody once every two weeks.

Regimen BH: administration at the loading dose of 6 mg/kg of theantibody once every week (weekly) for four weeks followed byadministration at the maintenance dose of 6 mg/kg of the antibody onceevery two weeks followed by administration at the modified maintenancedose of 12 mg/kg of the antibody once every two weeks.

Regimen BI: administration at the loading dose of 6 mg/kg of theantibody once every week (weekly) for four weeks followed byadministration at the maintenance dose of 12 mg/kg of the antibody onceevery four weeks (every month).

Regimen BJ: administration at the loading dose of 6 mg/kg of theantibody once every week (weekly) for four weeks followed byadministration at the maintenance dose of 12 mg/kg of the antibody onceevery four weeks (every month) followed by administration at themodified maintenance dose of 6 mg/kg of the antibody once every week(weekly).

Regimen BK: administration at the loading dose of 6 mg/kg of theantibody once every week (weekly) for four weeks followed byadministration at the maintenance dose of 12 mg/kg of the antibody onceevery four weeks (every month) followed by administration at themodified maintenance dose of 12 mg/kg of the antibody once every twoweeks.

Regimen BL: administration at the loading dose of 9 mg/kg of theantibody once every week (weekly) for two weeks followed byadministration at the maintenance dose of 3 mg/kg of the antibody onceevery week (weekly).

Regimen BM: administration at the loading dose of 9 mg/kg of theantibody once every week (weekly) for two weeks followed byadministration at the maintenance dose of 3 mg/kg of the antibody onceevery week (weekly) followed by administration at the modifiedmaintenance dose of 6 mg/kg of the antibody once every week (weekly).

Regimen BN: administration at the loading dose of 9 mg/kg of theantibody once every week (weekly) for two weeks followed byadministration at the maintenance dose of 3 mg/kg of the antibody onceevery week (weekly) followed by administration at the modifiedmaintenance dose of 12 mg/kg of the antibody once every two weeks.

Regimen BO: administration at the loading dose of 9 mg/kg of theantibody once every week (weekly) for two weeks followed byadministration at the maintenance dose of 6 mg/kg of the antibody onceevery two weeks.

Regimen BP: administration at the loading dose of 9 mg/kg of theantibody once every week (weekly) for two weeks followed byadministration at the maintenance dose of 6 mg/kg of the antibody onceevery two weeks followed by administration at the modified maintenancedose of 6 mg/kg of the antibody once every week (weekly).

Regimen BQ: administration at the loading dose of 9 mg/kg of theantibody once every week (weekly) for two weeks followed byadministration at the maintenance dose of 6 mg/kg of the antibody onceevery two weeks followed by administration at the modified maintenancedose of 12 mg/kg of the antibody once every two weeks.

Regimen BR: administration at the loading dose of 9 mg/kg of theantibody once every week (weekly) for two weeks followed byadministration at the maintenance dose of 12 mg/kg of the antibody onceevery four weeks (every month).

Regimen BS: administration at the loading dose of 9 mg/kg of theantibody once every week (weekly) for two weeks followed byadministration at the maintenance dose of 12 mg/kg of the antibody onceevery four weeks (every month) followed by administration at themodified maintenance dose of 6 mg/kg of the antibody once every week(weekly).

Regimen BT: administration at the loading dose of 9 mg/kg of theantibody once every week (weekly) for two weeks followed byadministration at the maintenance dose of 12 mg/kg of the antibody onceevery four weeks (every month) followed by administration at themodified maintenance dose of 12 mg/kg of the antibody once every twoweeks.

Regimen BU: administration at the loading dose of 12 mg/kg of theantibody once every two weeks for four weeks followed by administrationat the maintenance dose of 3 mg/kg of the antibody once every week(weekly).

Regimen BV: administration at the loading dose of 12 mg/kg of theantibody once every two weeks for four weeks followed by administrationat the maintenance dose of 3 mg/kg of the antibody once every week(weekly) followed by administration at the modified maintenance dose of6 mg/kg of the antibody once every week (weekly).

Regimen BW: administration at the loading dose of 12 mg/kg of theantibody once every two weeks for four weeks followed by administrationat the maintenance dose of 3 mg/kg of the antibody once every week(weekly) followed by administration at the modified maintenance dose of12 mg/kg of the antibody once every two weeks.

Regimen BX: administration at the loading dose of 12 mg/kg of theantibody once every two weeks for four weeks followed by administrationat the maintenance dose of 6 mg/kg of the antibody once every two weeks.

Regimen BY: administration at the loading dose of 12 mg/kg of theantibody once every two weeks for four weeks followed by administrationat the maintenance dose of 6 mg/kg of the antibody once every two weeksfollowed by administration at the modified maintenance dose of 6 mg/kgof the antibody once every week (weekly).

Regimen BZ: administration at the loading dose of 12 mg/kg of theantibody once every two weeks for four weeks followed by administrationat the maintenance dose of 6 mg/kg of the antibody once every two weeksfollowed by administration at the modified maintenance dose of 12 mg/kgof the antibody once every two weeks.

Regimen CA: administration at the loading dose of 12 mg/kg of theantibody once every two weeks for four weeks followed by administrationat the maintenance dose of 12 mg/kg of the antibody once every fourweeks (every month).

Regimen CB: administration at the loading dose of 12 mg/kg of theantibody once every two weeks for four weeks followed by administrationat the maintenance dose of 12 mg/kg of the antibody once every fourweeks (every month) followed by administration at the modifiedmaintenance dose of 6 mg/kg of the antibody once every week (weekly).

Regimen CC: administration at the loading dose of 12 mg/kg of theantibody once every two weeks for four weeks followed by administrationat the maintenance dose of 12 mg/kg of the antibody once every fourweeks (every month) followed by administration at the modifiedmaintenance dose of 12 mg/kg of the antibody once every two weeks.

Regimen CD: administration at the maintenance dose of 3 mg/kg of theantibody once every week (weekly).

Regimen CE: administration at the maintenance dose of 3 mg/kg of theantibody once every week (weekly) followed by administration at themodified maintenance dose of 4.5 mg/kg of the antibody once every week(weekly).

Regimen CF: administration at the maintenance dose of 3 mg/kg of theantibody once every week (weekly) followed by administration at themodified maintenance dose of 9 mg/kg of the antibody once every twoweeks.

Regimen CG: administration at the maintenance dose of 3 mg/kg of theantibody once every week (weekly) followed by administration at thefirst modified maintenance dose of 4.5 mg/kg of the antibody once everyweek (weekly) followed by administration at the second modifiedmaintenance dose of 6 mg/kg of the antibody once every week (weekly).

Regimen CH: administration at the maintenance dose of 3 mg/kg of theantibody once every week (weekly) followed by administration at thefirst modified maintenance dose of 4.5 mg/kg of the antibody once everyweek (weekly) followed by administration at the second modifiedmaintenance dose of 12 mg/kg of the antibody once every two weeks.

Regimen CI: administration at the maintenance dose of 3 mg/kg of theantibody once every week (weekly) followed by administration at thefirst modified maintenance dose of 9 mg/kg of the antibody once everytwo weeks followed by administration at the second modified maintenancedose of 6 mg/kg of the antibody once every week (weekly).

Regimen CJ: administration at the maintenance dose of 3 mg/kg of theantibody once every week (weekly) followed by administration at thefirst modified maintenance dose of 9 mg/kg of the antibody once everytwo weeks followed by administration at the second modified maintenancedose of 12 mg/kg of the antibody once every two weeks.

Regimen CK: administration at the maintenance dose of 3 mg/kg of theantibody once every week (weekly) followed by administration at themodified maintenance dose of 6 mg/kg of the antibody once every week(weekly).

Regimen CL: administration at the maintenance dose of 3 mg/kg of theantibody once every week (weekly) followed by administration at themodified maintenance dose of 12 mg/kg of the antibody once every twoweeks.

Regimen CM: administration at the maintenance dose of 6 mg/kg of theantibody once every two weeks.

Regimen CN: administration at the maintenance dose of 6 mg/kg of theantibody once every two weeks followed by administration at the modifiedmaintenance dose of 4.5 mg/kg of the antibody once every week (weekly).

Regimen CO: administration at the maintenance dose of 6 mg/kg of theantibody once every two weeks followed by administration at the modifiedmaintenance dose of 9 mg/kg of the antibody once every two weeks.

Regimen CP: administration at the maintenance dose of 6 mg/kg of theantibody once every two weeks followed by administration at the firstmodified maintenance dose of 4.5 mg/kg of the antibody once every week(weekly) followed by administration at the second modified maintenancedose of 6 mg/kg of the antibody once every week (weekly).

Regimen CQ: administration at the maintenance dose of 6 mg/kg of theantibody once every two weeks followed by administration at the firstmodified maintenance dose of 4.5 mg/kg of the antibody once every week(weekly) followed by administration at the second modified maintenancedose of 12 mg/kg of the antibody once every two weeks.

Regimen CR: administration at the maintenance dose of 6 mg/kg of theantibody once every two weeks followed by administration at the firstmodified maintenance dose of 9 mg/kg of the antibody once every twoweeks followed by administration at the second modified maintenance doseof 6 mg/kg of the antibody once every week (weekly).

Regimen CS: administration at the maintenance dose of 6 mg/kg of theantibody once every two weeks followed by administration at the firstmodified maintenance dose of 9 mg/kg of the antibody once every twoweeks followed by administration at the second modified maintenance doseof 12 mg/kg of the antibody once every two weeks.

Regimen CT: administration at the maintenance dose of 6 mg/kg of theantibody once every two weeks followed by administration at the modifiedmaintenance dose of 6 mg/kg of the antibody once every week (weekly).

Regimen CU: administration at the maintenance dose of 6 mg/kg of theantibody once every two weeks followed by administration at the modifiedmaintenance dose of 12 mg/kg of the antibody once every two weeks.

Regimen CV: administration at the maintenance dose of 12 mg/kg of theantibody once every four weeks (every month).

Regimen CW: administration at the maintenance dose of 12 mg/kg of theantibody once every four weeks (every month) followed by administrationat the modified maintenance dose of 4.5 mg/kg of the antibody once everyweek (weekly).

Regimen CX: administration at the maintenance dose of 12 mg/kg of theantibody once every four weeks (every month) followed by administrationat the modified maintenance dose of 9 mg/kg of the antibody once everytwo weeks.

Regimen CY: administration at the maintenance dose of 12 mg/kg of theantibody once every four weeks (every month) followed by administrationat the first modified maintenance dose of 4.5 mg/kg of the antibody onceevery week (weekly) followed by administration at the second modifiedmaintenance dose of 6 mg/kg of the antibody once every week (weekly).

Regimen CZ: administration at the maintenance dose of 12 mg/kg of theantibody once every four weeks (every month) followed by administrationat the first modified maintenance dose of 4.5 mg/kg of the antibody onceevery week (weekly) followed by administration at the second modifiedmaintenance dose of 12 mg/kg of the antibody once every two weeks.

Regimen DA: administration at the maintenance dose of 12 mg/kg of theantibody once every four weeks (every month) followed by administrationat the first modified maintenance dose of 9 mg/kg of the antibody onceevery two weeks followed by administration at the second modifiedmaintenance dose of 6 mg/kg of the antibody once every week (weekly).

Regimen DB: administration at the maintenance dose of 12 mg/kg of theantibody once every four weeks (every month) followed by administrationat the first modified maintenance dose of 9 mg/kg of the antibody onceevery two weeks followed by administration at the second modifiedmaintenance dose of 12 mg/kg of the antibody once every two weeks.

Regimen DC: administration at the maintenance dose of 12 mg/kg of theantibody once every four weeks (every month) followed by administrationat the modified maintenance dose of 6 mg/kg of the antibody once everyweek (weekly).

Regimen DD: administration at the maintenance dose of 12 mg/kg of theantibody once every four weeks (every month) followed by administrationat the modified maintenance dose of 12 mg/kg of the antibody once everytwo weeks.

Regimen DE: administration at the maintenance dose of 4.5 mg/kg of theantibody once every week (weekly).

Regimen DF: administration at the maintenance dose of 4.5 mg/kg of theantibody once every week (weekly) followed by administration at themodified maintenance dose of 6 mg/kg of the antibody once every week(weekly).

Regimen DG: administration at the maintenance dose of 4.5 mg/kg of theantibody once every week (weekly) followed by administration at themodified maintenance dose of 12 mg/kg of the antibody once every twoweeks.

Regimen DH: administration at the maintenance dose of 9 mg/kg of theantibody once every two weeks.

Regimen DI: administration at the maintenance dose of 9 mg/kg of theantibody once every two weeks followed by administration at the modifiedmaintenance dose of 6 mg/kg of the antibody once every week (weekly).

Regimen DJ: administration at the maintenance dose of 9 mg/kg of theantibody once every two weeks followed by administration at the modifiedmaintenance dose of 12 mg/kg of the antibody once every two weeks.

Regimen DK: administration at the maintenance dose of 6 mg/kg of theantibody once every week (weekly).

Regimen DL: administration at the maintenance dose of 12 mg/kg of theantibody once every two weeks.

Regimen DM: administration at the loading dose of 3 mg/kg of theantibody once every week (weekly) for four weeks followed byadministration at the maintenance dose of 1.5 mg/kg of the antibody onceevery week (weekly) followed by administration at the modifiedmaintenance dose of 2.25 mg/kg of the antibody once every week (weekly).

Regimen DN: administration at the loading dose of 3 mg/kg of theantibody once every week (weekly) for four weeks followed byadministration at the maintenance dose of 1.5 mg/kg of the antibody onceevery week (weekly) followed by administration at the first modifiedmaintenance dose of 2.25 mg/kg of the antibody once every week (weekly)followed by administration at the second modified maintenance dose of 3mg/kg of the antibody once every week (weekly).

Regimen DO: administration at the loading dose of 3 mg/kg of theantibody once every week (weekly) for four weeks followed byadministration at the maintenance dose of 1.5 mg/kg of the antibody onceevery week (weekly) followed by administration at the first modifiedmaintenance dose of 2.25 mg/kg of the antibody once every week (weekly)followed by administration at the second modified maintenance dose of 3mg/kg of the antibody once every week (weekly) followed byadministration at the third modified maintenance dose of 4.5 mg/kg ofthe antibody once every week (weekly).

Regimen DP: administration at the loading dose of 3 mg/kg of theantibody once every week (weekly) for four weeks followed byadministration at the maintenance dose of 1.5 mg/kg of the antibody onceevery week (weekly) followed by administration at the first modifiedmaintenance dose of 2.25 mg/kg of the antibody once every week (weekly)followed by administration at the second modified maintenance dose of 3mg/kg of the antibody once every week (weekly) followed byadministration at the third modified maintenance dose of 4.5 mg/kg ofthe antibody once every week (weekly) followed by administration at thefourth modified maintenance dose of 6 mg/kg of the antibody once everyweek (weekly).

Regimen DQ: administration at the loading dose of 3 mg/kg of theantibody once every week (weekly) for four weeks followed byadministration at the maintenance dose of 1.5 mg/kg of the antibody onceevery week (weekly) followed by administration at the first modifiedmaintenance dose of 2.25 mg/kg of the antibody once every week (weekly)followed by administration at the second modified maintenance dose of 3mg/kg of the antibody once every week (weekly) followed byadministration at the third modified maintenance dose of 6 mg/kg of theantibody once every week (weekly).

Regimen DR: administration at the loading dose of 3 mg/kg of theantibody once every week (weekly) for four weeks followed byadministration at the maintenance dose of 1.5 mg/kg of the antibody onceevery week (weekly) followed by administration at the first modifiedmaintenance dose of 2.25 mg/kg of the antibody once every week (weekly)followed by administration at the second modified maintenance dose of4.5 mg/kg of the antibody once every week (weekly).

Regimen DS: administration at the loading dose of 3 mg/kg of theantibody once every week (weekly) for four weeks followed byadministration at the maintenance dose of 1.5 mg/kg of the antibody onceevery week (weekly) followed by administration at the first modifiedmaintenance dose of 2.25 mg/kg of the antibody once every week (weekly)followed by administration at the second modified maintenance dose of4.5 mg/kg of the antibody once every week (weekly) followed byadministration at the third modified maintenance dose of 6 mg/kg of theantibody once every week (weekly).

Regimen DT: administration at the loading dose of 3 mg/kg of theantibody once every week (weekly) for four weeks followed byadministration at the maintenance dose of 1.5 mg/kg of the antibody onceevery week (weekly) followed by administration at the first modifiedmaintenance dose of 3 mg/kg of the antibody once every week (weekly)followed by administration at the second modified maintenance dose of4.5 mg/kg of the antibody once every week (weekly).

Regimen DU: administration at the loading dose of 3 mg/kg of theantibody once every week (weekly) for four weeks followed byadministration at the maintenance dose of 1.5 mg/kg of the antibody onceevery week (weekly) followed by administration at the first modifiedmaintenance dose of 3 mg/kg of the antibody once every week (weekly)followed by administration at the second modified maintenance dose of4.5 mg/kg of the antibody once every week (weekly) followed byadministration at the third modified maintenance dose of 6 mg/kg of theantibody once every week (weekly).

Regimen DV: administration at the loading dose of 3 mg/kg of theantibody once every week (weekly) for four weeks followed byadministration at the maintenance dose of 1.5 mg/kg of the antibody onceevery week (weekly) followed by administration at the first modifiedmaintenance dose of 3 mg/kg of the antibody once every week (weekly)followed by administration at the second modified maintenance dose of 6mg/kg of the antibody once every week (weekly).

Regimen DW: administration at the loading dose of 3 mg/kg of theantibody once every week (weekly) for four weeks followed byadministration at the maintenance dose of 2.25 mg/kg of the antibodyonce every week (weekly).

Regimen DX: administration at the loading dose of 3 mg/kg of theantibody once every week (weekly) for four weeks followed byadministration at the maintenance dose of 2.25 mg/kg of the antibodyonce every week (weekly) followed by administration at the modifiedmaintenance dose of 3 mg/kg of the antibody once every week (weekly).

Regimen DY: administration at the loading dose of 3 mg/kg of theantibody once every week (weekly) for four weeks followed byadministration at the maintenance dose of 2.25 mg/kg of the antibodyonce every week (weekly) followed by administration at the firstmodified maintenance dose of 3 mg/kg of the antibody once every week(weekly) followed by administration at the second modified maintenancedose of 4.5 mg/kg of the antibody once every week (weekly).

Regimen DZ: administration at the loading dose of 3 mg/kg of theantibody once every week (weekly) for four weeks followed byadministration at the maintenance dose of 2.25 mg/kg of the antibodyonce every week (weekly) followed by administration at the firstmodified maintenance dose of 3 mg/kg of the antibody once every week(weekly) followed by administration at the second modified maintenancedose of 4.5 mg/kg of the antibody once every week (weekly) followed byadministration at the third modified maintenance dose of 6 mg/kg of theantibody once every week (weekly).

Regimen EA: administration at the loading dose of 3 mg/kg of theantibody once every week (weekly) for four weeks followed byadministration at the maintenance dose of 2.25 mg/kg of the antibodyonce every week (weekly) followed by administration at the firstmodified maintenance dose of 3 mg/kg of the antibody once every week(weekly) followed by administration at the second modified maintenancedose of 6 mg/kg of the antibody once every week (weekly).

Regimen EB: administration at the loading dose of 3 mg/kg of theantibody once every week (weekly) for four weeks followed byadministration at the maintenance dose of 2.25 mg/kg of the antibodyonce every week (weekly) followed by administration at the modifiedmaintenance dose of 4.5 mg/kg of the antibody once every week (weekly).

Regimen EC: administration at the loading dose of 3 mg/kg of theantibody once every week (weekly) for four weeks followed byadministration at the maintenance dose of 2.25 mg/kg of the antibodyonce every week (weekly) followed by administration at the firstmodified maintenance dose of 4.5 mg/kg of the antibody once every week(weekly) followed by administration at the second modified maintenancedose of 6 mg/kg of the antibody once every week (weekly).

Regimen ED: (I) administration at the loading dose of (I-i) 3 mg/kg ofthe antibody once every week (weekly) for four weeks, (I-ii) 4.5 mg/kgof the antibody once every week (weekly) for two weeks, or (I-iii) 6mg/kg of the antibody once every two weeks for four weeks, followed by(II) administration at the maintenance dose of (II-i) 1.5 mg/kg of theantibody once every week (weekly), (II-ii) 3 mg/kg of the antibody onceevery two weeks, or (II-iii) 6 mg/kg of the antibody once every fourweeks (every month), followed by (III) administration at the modifiedmaintenance dose of (III-i) 2.25 mg/kg of the antibody once every week(weekly), (III-ii) 4.5 mg/kg of the antibody once every two weeks, or(III-iii) 9 mg/kg of the antibody once every four weeks (every month).

Regimen EE: (I) administration at the loading dose of (I-i) 3 mg/kg ofthe antibody once every week (weekly) for four weeks, (I-ii) 4.5 mg/kgof the antibody once every week (weekly) for two weeks, or (I-iii) 6mg/kg of the antibody once every two weeks for four weeks, followed by(II) administration at the maintenance dose of (II-i) 1.5 mg/kg of theantibody once every week (weekly), (II-ii) 3 mg/kg of the antibody onceevery two weeks, or (II-iii) 6 mg/kg of the antibody once every fourweeks (every month), followed by (III) administration at the firstmodified maintenance dose of (III-i) 2.25 mg/kg of the antibody onceevery week (weekly), (III-ii) 4.5 mg/kg of the antibody once every twoweeks, or (III-iii) 9 mg/kg of the antibody once every four weeks (everymonth), followed by (IV) administration at the second modifiedmaintenance dose of (IV-i) 3 mg/kg of the antibody once every week(weekly), (IV-ii) 6 mg/kg of the antibody once every two weeks, or(IV-iii) 12 mg/kg of the antibody once every four weeks (every month).

Regimen EF: (I) administration at the loading dose of (I-i) 3 mg/kg ofthe antibody once every week (weekly) for four weeks, (I-ii) 4.5 mg/kgof the antibody once every week (weekly) for two weeks, or (I-iii) 6mg/kg of the antibody once every two weeks for four weeks, followed by(II) administration at the maintenance dose of (II-i) 1.5 mg/kg of theantibody once every week (weekly), (II-ii) 3 mg/kg of the antibody onceevery two weeks, or (II-iii) 6 mg/kg of the antibody once every fourweeks (every month), followed by (III) administration at the firstmodified maintenance dose of (III-i) 2.25 mg/kg of the antibody onceevery week (weekly), (III-ii) 4.5 mg/kg of the antibody once every twoweeks, or (III-iii) 9 mg/kg of the antibody once every four weeks (everymonth), followed by (IV) administration at the second modifiedmaintenance dose of (IV-i) 3 mg/kg of the antibody once every week(weekly), (IV-ii) 6 mg/kg of the antibody once every two weeks, or(IV-iii) 12 mg/kg of the antibody once every four weeks (every month),followed by (V) administration at the third modified maintenance dose of(V-i) 4.5 mg/kg of the antibody once every week (weekly), or (V-ii) 9mg/kg of the antibody once every two weeks.

Regimen EG: (I) administration at the loading dose of (I-i) 3 mg/kg ofthe antibody once every week (weekly) for four weeks, (I-ii) 4.5 mg/kgof the antibody once every week (weekly) for two weeks, or (I-iii) 6mg/kg of the antibody once every two weeks for four weeks, followed by(II) administration at the maintenance dose of (II-i) 1.5 mg/kg of theantibody once every week (weekly), (II-ii) 3 mg/kg of the antibody onceevery two weeks, or (II-iii) 6 mg/kg of the antibody once every fourweeks (every month), followed by (III) administration at the firstmodified maintenance dose of (III-i) 2.25 mg/kg of the antibody onceevery week (weekly), (III-ii) 4.5 mg/kg of the antibody once every twoweeks, or (III-iii) 9 mg/kg of the antibody once every four weeks (everymonth), followed by (IV) administration at the second modifiedmaintenance dose of (IV-i) 3 mg/kg of the antibody once every week(weekly), (IV-ii) 6 mg/kg of the antibody once every two weeks, or(IV-iii) 12 mg/kg of the antibody once every four weeks (every month),followed by (V) administration at the third modified maintenance dose of(V-i) 4.5 mg/kg of the antibody once every week (weekly), or (V-ii) 9mg/kg of the antibody once every two weeks, followed by (VI)administration at the fourth modified maintenance dose of (VI-i) 6 mg/kgof the antibody once every week (weekly), or (VI-ii) 12 mg/kg of theantibody once every two weeks.

Regimen EH: (I) administration at the loading dose of (I-i) 3 mg/kg ofthe antibody once every week (weekly) for four weeks, (I-ii) 4.5 mg/kgof the antibody once every week (weekly) for two weeks, or (I-iii) 6mg/kg of the antibody once every two weeks for four weeks, followed by(II) administration at the maintenance dose of (II-i) 1.5 mg/kg of theantibody once every week (weekly), (II-ii) 3 mg/kg of the antibody onceevery two weeks, or (II-iii) 6 mg/kg of the antibody once every fourweeks (every month), followed by (III) administration at the firstmodified maintenance dose of (III-i) 2.25 mg/kg of the antibody onceevery week (weekly), (III-ii) 4.5 mg/kg of the antibody once every twoweeks, or (III-iii) 9 mg/kg of the antibody once every four weeks (everymonth), followed by (IV) administration at the second modifiedmaintenance dose of (IV-i) 3 mg/kg of the antibody once every week(weekly), (IV-ii) 6 mg/kg of the antibody once every two weeks, or(IV-iii) 12 mg/kg of the antibody once every four weeks (every month),followed by (V) administration at the third modified maintenance dose of(V-i) 6 mg/kg of the antibody once every week (weekly), or (V-ii) 12mg/kg of the antibody once every two weeks.

Regimen EI: (I) administration at the loading dose of (I-i) 3 mg/kg ofthe antibody once every week (weekly) for four weeks, (I-ii) 4.5 mg/kgof the antibody once every week (weekly) for two weeks, or (I-iii) 6mg/kg of the antibody once every two weeks for four weeks, followed by(II) administration at the maintenance dose of (II-i) 1.5 mg/kg of theantibody once every week (weekly), (II-ii) 3 mg/kg of the antibody onceevery two weeks, or (II-iii) 6 mg/kg of the antibody once every fourweeks (every month), followed by (III) administration at the firstmodified maintenance dose of (III-i) 2.25 mg/kg of the antibody onceevery week (weekly), (III-ii) 4.5 mg/kg of the antibody once every twoweeks, or (III-iii) 9 mg/kg of the antibody once every four weeks (everymonth), followed by (IV) administration at the second modifiedmaintenance dose of (IV-i) 4.5 mg/kg of the antibody once every week(weekly), or (IV-ii) 9 mg/kg of the antibody once every two weeks.

Regimen EJ: (I) administration at the loading dose of (I-i) 3 mg/kg ofthe antibody once every week (weekly) for four weeks, (I-ii) 4.5 mg/kgof the antibody once every week (weekly) for two weeks, or (I-iii) 6mg/kg of the antibody once every two weeks for four weeks, followed by(II) administration at the maintenance dose of (II-i) 1.5 mg/kg of theantibody once every week (weekly), (II-ii) 3 mg/kg of the antibody onceevery two weeks, or (II-iii) 6 mg/kg of the antibody once every fourweeks (every month), followed by (III) administration at the firstmodified maintenance dose of (III-i) 2.25 mg/kg of the antibody onceevery week (weekly), (III-ii) 4.5 mg/kg of the antibody once every twoweeks, or (III-iii) 9 mg/kg of the antibody once every four weeks (everymonth), followed by (IV) administration at the second modifiedmaintenance dose of (IV-i) 4.5 mg/kg of the antibody once every week(weekly), or (IV-ii) 9 mg/kg of the antibody once every two weeks,followed by (V) administration at the third modified maintenance dose of(V-i) 6 mg/kg of the antibody once every week (weekly), or (V-ii) 12mg/kg of the antibody once every two weeks.

Regimen EK: (I) administration at the loading dose of (I-i) 3 mg/kg ofthe antibody once every week (weekly) for four weeks, (I-ii) 4.5 mg/kgof the antibody once every week (weekly) for two weeks, or (I-iii) 6mg/kg of the antibody once every two weeks for four weeks, followed by(II) administration at the maintenance dose of (II-i) 1.5 mg/kg of theantibody once every week (weekly), (II-ii) 3 mg/kg of the antibody onceevery two weeks, or (II-iii) 6 mg/kg of the antibody once every fourweeks (every month), followed by (III) administration at the firstmodified maintenance dose of (III-i) 3 mg/kg of the antibody once everyweek (weekly), (III-ii) 6 mg/kg of the antibody once every two weeks, or(III-iii) 12 mg/kg of the antibody once every four weeks (every month),followed by (IV) administration at the second modified maintenance doseof (IV-i) 4.5 mg/kg of the antibody once every week (weekly), or (IV-ii)9 mg/kg of the antibody once every two weeks.

Regimen EL: (I) administration at the loading dose of (I-i) 3 mg/kg ofthe antibody once every week (weekly) for four weeks, (I-ii) 4.5 mg/kgof the antibody once every week (weekly) for two weeks, or (I-iii) 6mg/kg of the antibody once every two weeks for four weeks, followed by(II) administration at the maintenance dose of (II-i) 1.5 mg/kg of theantibody once every week (weekly), (II-ii) 3 mg/kg of the antibody onceevery two weeks, or (II-iii) 6 mg/kg of the antibody once every fourweeks (every month), followed by (III) administration at the firstmodified maintenance dose of (III-i) 3 mg/kg of the antibody once everyweek (weekly), (III-ii) 6 mg/kg of the antibody once every two weeks, or(III-iii) 12 mg/kg of the antibody once every four weeks (every month),followed by (IV) administration at the second modified maintenance doseof (IV-i) 4.5 mg/kg of the antibody once every week (weekly), or (IV-ii)9 mg/kg of the antibody once every two weeks, followed by (V)administration at the third modified maintenance dose of (V-i) 6 mg/kgof the antibody once every week (weekly), or (V-ii) 12 mg/kg of theantibody once every two weeks.

Regimen EM: (I) administration at the loading dose of (I-i) 3 mg/kg ofthe antibody once every week (weekly) for four weeks, (I-ii) 4.5 mg/kgof the antibody once every week (weekly) for two weeks, or (I-iii) 6mg/kg of the antibody once every two weeks for four weeks, followed by(II) administration at the maintenance dose of (II-i) 1.5 mg/kg of theantibody once every week (weekly), (II-ii) 3 mg/kg of the antibody onceevery two weeks, or (II-iii) 6 mg/kg of the antibody once every fourweeks (every month), followed by (III) administration at the firstmodified maintenance dose of (III-i) 3 mg/kg of the antibody once everyweek (weekly), (III-ii) 6 mg/kg of the antibody once every two weeks, or(III-iii) 12 mg/kg of the antibody once every four weeks (every month),followed by (IV) administration at the second modified maintenance doseof (IV-i) 6 mg/kg of the antibody once every week (weekly), or (IV-ii)12 mg/kg of the antibody once every two weeks.

Regimen EN: (I) administration at the loading dose of (I-i) 3 mg/kg ofthe antibody once every week (weekly) for four weeks, (I-ii) 4.5 mg/kgof the antibody once every week (weekly) for two weeks, or (I-iii) 6mg/kg of the antibody once every two weeks for four weeks, followed by(II) administration at the maintenance dose of (II-i) 2.25 mg/kg of theantibody once every week (weekly), (II-ii) 4.5 mg/kg of the antibodyonce every two weeks, or (II-iii) 9 mg/kg of the antibody once everyfour weeks (every month).

Regimen EO: (I) administration at the loading dose of (I-i) 3 mg/kg ofthe antibody once every week (weekly) for four weeks, (I-ii) 4.5 mg/kgof the antibody once every week (weekly) for two weeks, or (I-iii) 6mg/kg of the antibody once every two weeks for four weeks, followed by(II) administration at the maintenance dose of (II-i) 2.25 mg/kg of theantibody once every week (weekly), (II-ii) 4.5 mg/kg of the antibodyonce every two weeks, or (II-iii) 9 mg/kg of the antibody once everyfour weeks (every month), followed by (III) administration at themodified maintenance dose of (III-i) 3 mg/kg of the antibody once everyweek (weekly), (III-ii) 6 mg/kg of the antibody once every two weeks, or(III-iii) 12 mg/kg of the antibody once every four weeks (every month).

Regimen EP: (I) administration at the loading dose of (I-i) 3 mg/kg ofthe antibody once every week (weekly) for four weeks, (I-ii) 4.5 mg/kgof the antibody once every week (weekly) for two weeks, or (I-iii) 6mg/kg of the antibody once every two weeks for four weeks, followed by(II) administration at the maintenance dose of (II-i) 2.25 mg/kg of theantibody once every week (weekly), (II-ii) 4.5 mg/kg of the antibodyonce every two weeks, or (II-iii) 9 mg/kg of the antibody once everyfour weeks (every month), followed by (III) administration at the firstmodified maintenance dose of (III-i) 3 mg/kg of the antibody once everyweek (weekly), (III-ii) 6 mg/kg of the antibody once every two weeks, or(III-iii) 12 mg/kg of the antibody once every four weeks (every month),followed by (IV) administration at the second modified maintenance doseof (IV-i) 4.5 mg/kg of the antibody once every week (weekly), or (IV-ii)9 mg/kg of the antibody once every two weeks.

Regimen EQ: (I) administration at the loading dose of (I-i) 3 mg/kg ofthe antibody once every week (weekly) for four weeks, (I-ii) 4.5 mg/kgof the antibody once every week (weekly) for two weeks, or (I-iii) 6mg/kg of the antibody once every two weeks for four weeks, followed by(II) administration at the maintenance dose of (II-i) 2.25 mg/kg of theantibody once every week (weekly), (II-ii) 4.5 mg/kg of the antibodyonce every two weeks, or (II-iii) 9 mg/kg of the antibody once everyfour weeks (every month), followed by (III) administration at the firstmodified maintenance dose of (III-i) 3 mg/kg of the antibody once everyweek (weekly), (III-ii) 6 mg/kg of the antibody once every two weeks, or(III-iii) 12 mg/kg of the antibody once every four weeks (every month),followed by (IV) administration at the second modified maintenance doseof (IV-i) 4.5 mg/kg of the antibody once every week (weekly), or (IV-ii)9 mg/kg of the antibody once every two weeks, followed by (V)administration at the third modified maintenance dose of (V-i) 6 mg/kgof the antibody once every week (weekly), or (V-ii) 12 mg/kg of theantibody once every two weeks.

Regimen ER: (I) administration at the loading dose of (I-i) 3 mg/kg ofthe antibody once every week (weekly) for four weeks, (I-ii) 4.5 mg/kgof the antibody once every week (weekly) for two weeks, or (I-iii) 6mg/kg of the antibody once every two weeks for four weeks, followed by(II) administration at the maintenance dose of (II-i) 2.25 mg/kg of theantibody once every week (weekly), (II-ii) 4.5 mg/kg of the antibodyonce every two weeks, or (II-iii) 9 mg/kg of the antibody once everyfour weeks (every month), followed by (III) administration at the firstmodified maintenance dose of (III-i) 3 mg/kg of the antibody once everyweek (weekly), (III-ii) 6 mg/kg of the antibody once every two weeks, or(III-iii) 12 mg/kg of the antibody once every four weeks (every month),followed by (IV) administration at the second modified maintenance doseof (IV-i) 6 mg/kg of the antibody once every week (weekly), or (IV-ii)12 mg/kg of the antibody once every two weeks.

Regimen ES: (I) administration at the loading dose of (I-i) 3 mg/kg ofthe antibody once every week (weekly) for four weeks, (I-ii) 4.5 mg/kgof the antibody once every week (weekly) for two weeks, or (I-iii) 6mg/kg of the antibody once every two weeks for four weeks, followed by(II) administration at the maintenance dose of (II-i) 2.25 mg/kg of theantibody once every week (weekly), (II-ii) 4.5 mg/kg of the antibodyonce every two weeks, or (II-iii) 9 mg/kg of the antibody once everyfour weeks (every month), followed by (III) administration at themodified maintenance dose of (III-i) 4.5 mg/kg of the antibody onceevery week (weekly), or (III-ii) 9 mg/kg of the antibody once every twoweeks.

Regimen ET: (I) administration at the loading dose of (I-i) 3 mg/kg ofthe antibody once every week (weekly) for four weeks, (I-ii) 4.5 mg/kgof the antibody once every week (weekly) for two weeks, or (I-iii) 6mg/kg of the antibody once every two weeks for four weeks, followed by(II) administration at the maintenance dose of (II-i) 2.25 mg/kg of theantibody once every week (weekly), (II-ii) 4.5 mg/kg of the antibodyonce every two weeks, or (II-iii) 9 mg/kg of the antibody once everyfour weeks (every month), followed by (III) administration at the firstmodified maintenance dose of (III-i) 4.5 mg/kg of the antibody onceevery week (weekly), or (III-ii) 9 mg/kg of the antibody once every twoweeks, followed by (IV) administration at the second modifiedmaintenance dose of (IV-i) 6 mg/kg of the antibody once every week(weekly), or (IV-ii) 12 mg/kg of the antibody once every two weeks.

In some embodiments, regimens of the invention can be applicable forpatients who suffer from bleeding, or excessive bleeding. The regimensof the invention can be applicable in a method for preventing and/ortreating bleeding in such patients, or for increasing blood clottingactivity in such patients, or for reducing excessive bleeding in suchpatients. Here, “preventing” or “treating” bleeding refers to reducingthe incidence of bleeding or reducing the likelihood of bleeding in apatient. In certain embodiments, excessive bleeding in such patients iscaused by a decrease or deficiency in the activity of FVIII and/orFVIIIa. In a certain embodiment, patents who suffer from bleeding havehemophilia, which may be hemophilia A or severe hemophilia A.

In some embodiments, regimens of the invention can be applicable forpatients with hemophilia A and preferably patients with hemophilia Ahaving FVIII inhibitors and/or patients with hemophilia A not havingFVIII inhibitors.

In some embodiment, regimens of the invention can be applicable forpatients with severe hemophilia A.

In some embodiments, regimens of the invention can be applicable foradult patients, and/or pediatric patients and/or such special populationof patients likely to exhibit lower exposure.

The dosage regimen is determined, for example, by considering theeffects and safety. Furthermore, the dosage regimen is determined byconsidering the convenience of the patient, within the range that doesnot impair the effectiveness and safety. For example, the dosage regimenfor a hemophilia A patient can be determined by considering the effectsof preventing bleeding in patients and clinically acceptable safety.

A disease accompanying bleeding or a disease caused by bleeding mayinclude a disease that develops and/or progresses due to a decrease ordeficiency in the activity of FVIII and/or FVIIIa.

A disease that develops and/or progresses due to a decrease ordeficiency in the activity of FVIII and/or FVIIIa is, for example,hemophilia A, hemophilia A with emergence of an inhibitor againstFVIII/FVIIIa, acquired hemophilia A, and von Willebrand disease, but thedisease is not particularly limited thereto.

In some embodiments, regimens of the invention can be applicable forpreventing bleeding episodes and reducing the frequency of bleedingepisodes in congenital FV111-deficient patients with inhibitors.

In some embodiments, regimens of the invention can be applicable forpreventing bleeding episodes and reducing the frequency of bleedingepisodes in congenital FV111-deficient patients without inhibitors.

In some embodiments, regimens of the invention can be applicable forpreventing bleeding episodes and reducing the frequency of bleedingepisodes in acquired FV111-deficient patients with inhibitors.

In some embodiments, regimens of the invention can be applicable forpreventing bleeding episodes and reducing the frequency of bleedingepisodes in acquired FV111-deficient patients without inhibitors.

In some embodiments, regimens of the invention can be applicable forpreventing bleeding episodes and reducing the frequency of bleedingepisodes in congenital von Willebrand factor-deficient patients.

In some embodiments, regimens of the invention can be applicable forpreventing bleeding episodes and reducing the frequency of bleedingepisodes in acquired von Willebrand factor-deficient patients.

The term “inhibitor patient” as used herein refers to a patient withhemophilia A having FVIII inhibitors.

The term “non-inhibitor patient” as used herein refers to a patient withhemophilia A not having FVIII inhibitors.

The present invention provides a product comprising at least (i) acontainer; (ii) a pharmaceutical composition in a container, whichcomprises a bispecific antigen-binding molecule that recognizes (a) FIXand/or FIXa and (b) FX and/or FXa; and (iii) a document instructingadministration of the antigen-binding molecule according to any one ofthe dosing regimens described above. In addition, a label, syringe,syringe needle, pharmaceutically acceptable medium, alcohol-soakedcotton, adhesive bandage, and such may be packaged in the product. Thecontainer is, for example, a bottle, a glass bottle, or a syringe, andcan be produced from various materials such as glass or plastic.Administration-supporting devices may be attached to the product. Apharmaceutical composition is stored in the container, and the mouth ofthe container is sealed with a rubber stopper or such. For example, alabel indicating that the pharmaceutical composition is to be used forpreventing or treating selected pathological conditions is attached tothe container. The document of (iii) may include instructions thatspecify the loading dose, maintenance dose, administration frequency orintervals, according to the dosing regimens as described above.

Treatment of hemophilia refers to, for example, stopping bleeding byadministering the composition to a hemophilia patient who is actuallyshowing bleeding symptoms (treatment of bleeding) and/or reducing thebleeding frequency by administering the composition to a patient who hadshown bleeding to prevent manifestation of bleeding symptoms in advance(prevention of bleeding), but it is not limited thereto. Treatment andprevention of bleeding may be understood as having the same meaning incertain cases and such treatment and prevention of bleeding may becalled prophylaxis therapy or regular administration therapy of atherapeutic agent (the bispecific antigen-binding molecules of thepresent invention).

Prevention of hemophilia refers to, for example, reducing the incidenceof hemophilia or reducing the likelihood of hemophilia.

Herein, bleeding that is examined and counted as the number of bleedingevents in a patient is, for example, bleeding that required hemostatictreatment by coagulation factor formulations. Coagulation factorformulations refer to, for example, FVIII formulations and bypassingagents (activated prothrombin complex formulations, recombinant FVIIaformulations, and such).

The number of bleedings per year (the Annualized Bleeding Rate (ABR)) iscalculated as, for example: (number of bleeding events×365.25)/number ofdays of observation.

The present invention provides a pharmaceutical composition comprising abispecific antigen-binding molecule which recognizes (a) FIX and/or FIXaand (b) FX and/or FXa, as a more effective pharmaceutical compositionfor preventing and/or treating bleeding, a disease accompanyingbleeding, or a disease caused by bleeding, the disease including thosethat develops and/or progresses due to a decrease or deficiency in theactivity of FVIII and/or FVIIIa, or a dosage regimen thereof.

All prior art references cited herein are incorporated by reference intothis description.

EXAMPLES

The present invention is specifically illustrated below with referenceto Examples, but it is not construed as being limited thereto.

Example 1 Efficacious Dosing Regimens With Administration IntervalExtension and/or Dose Up-Titration Dose-Exposure-Response ModelDevelopment

A population pharmacokinetic (PopPK) model of emicizumab was developedusing the quantifiable plasma emicizumab concentration data from 42healthy subjects (NPL 8) and 18 patients with hemophilia A having or nothaving FVIII inhibitors (NPLs 9 and 10). In addition, theexposure-response relationship on the bleeding-prophylactic efficacy ofemicizumab was quantitatively characterized based on a repeatedtime-to-event (RTTE) modeling approach using the bleeding onset datafrom the same 18 patients (NPLs 9 and 10).

A one-compartment model with first-order absorption and first-orderelimination was employed as the structural PopPK model to describe theplasma emicizumab concentration-time profile. The parameter estimates ofthe PopPK model including covariate effects are listed in Table 1.

TABLE 1 Parameter Estimates of the Population Pharmacokinetic ModelParameter Unit Estimate^(a)) Model structure CL/F^(b)) L/day 0.222V_(d)/F^(b)) L 10.2 t_(1/2, abs) day 1.56 Covariate effect Onset time ofthe effect of influential ADA day 33.4 on CL/F after emicizumabadministration Effect of influential ADA on CL/F^(c)) — 2.01 Effect ofBW on CL/F^(d)) — 0.75 (fixed) Effect of BW on V_(d)/F^(d)) —   1(fixed) Effect of PAT on CL/F^(c)) — 0.232 Effect of PAT on V_(d)/F^(c))— 0.175 Inter-individual variability^(e)) Variance for CL/F — 0.0737Variance for V_(d)/F — 0.0455 Variance for t_(1/2, abs) — 0.502Covariance for CL/F and V_(d)/F — 0.0278 Residual unexplainedvariability^(f)) Additive error^(g)) μg/mL 0.0149 Proportionalerror^(h)) % 12.8 CL/F: apparent total clearance, V_(d)/F: apparentvolume of distribution, t_(1/2, abs): first-order absorption half-life,ADA: influential anti-drug antibodies, BW: body weight, PAT: patient.^(a))estimated using NONMEM software version 7.2.0 (ICON DevelopmentSolutions, Ellicott City, MD, USA), ^(b))standardized by a typical bodyweight of 70 kg, ^(c))parameterized as log-transformed geometric meanratio, ^(d))parameterized as allometric exponent (assumed to work in apower manner), ^(e))assumed to follow an exponential error model,^(f))assumed to follow a combined additive plus proportional errormodel, ^(g))parameterized as standard deviation, ^(h))parameterized ascoefficient of variation.

RTTE modeling dealt with the bleeding events that occurred both before(i.e., for approximately 6 months) and after the start of emicizumabadministration and required the on-demand use of coagulation factorproducts, regardless of the bleeding site. A time-varying hazard modelas the structural RTTE model consisted of a constant baseline hazard(lambda) to account for the bleeding rate when treated with theon-demand therapy with coagulation factor products and an E_(max) modelto account for the bleeding-prophylactic effect of emicizumab as afunction of plasma emicizumab concentration. The model equation of theRTTE model is illustrated below, and the parameter estimates are listedin Table 2.

$\begin{matrix}{{h(t)} = {\lambda \times \left( {1 - \frac{\frac{C_{p}(t)}{EC_{50}} + E_{PLX}}{1 + \frac{C_{p}(t)}{EC_{50}} + E_{PLX}}} \right)}} & \left\lbrack {{Math}.1} \right\rbrack\end{matrix}$

h(t): hazard on bleeding onset at a time of t, C_(p)(t): populationpharmacokinetic model-predicted plasma emicizumab concentration at atime of t, λ(lambda); baseline hazard on bleeding onset (annual bleedingrate). EC₅₀: plasma emicizumab concentration to achieve a half of themaximum prophylactic effect on bleeding onset, E_(PLX): effect of theprophylactic therapy with coagulation factor products when ongoing.

TABLE 2 Parameter Estimates of the Repeated Time-to-Event ModelParameter Unit Estimate^(a)) Model structure λ (lambda) count/year 21.9EC₅₀ μg/mL 1.19 E_(PLX) — 0.314 Inter-individual variability^(b))Variance for λ — 0.340 Variance for EC₅₀ — 2.53 lambda: baseline hazardon bleeding onset (annual bleeding rate), EC₅₀: plasma emicizumabconcentration to achieve a half of the maximum prophylactic effect onbleeding onset, E_(PLX): effect of the prophylactic therapy withcoagulation factor products when ongoing. ^(a))estimated using NONMEMsoftware version 7.2.0 (ICON Development Solutions, Ellicott City, MD,USA), ^(b))assumed to follow an exponential error model.

Determination of Efficacious Exposure and Justification of DoseUp-Titration

The RTTE model-simulated relationship between annual bleeding rate (ABR)and plasma emicizumab concentration is shown in FIG. 1 . A plasmaemicizumab concentration of 45 micro g/mL or more is expected to achievea median ABR of zero indicating no bleeding onset for a year in 50% ormore of patients.

Further improvement in bleeding-prophylactic efficacy outcome is notexpected at plasma emicizumab concentrations of 45 micro g/mL or more interms of median ABR. However, due to the inter-individual variability indrug effect and baseline ABR, there would remain considerableproportions of patients with ABR of >0 even at such plasma emicizumabconcentrations. Therefore, it is likely that increasing plasmaemicizumab concentration (emicizumab dose) results in further reducedABR in patients with imperfect bleeding control. In addition, in case ofa special population likely to exhibit lower exposure (e.g., pediatricpatients), increasing emicizumab dose should make sense to provideincreased plasma emicizumab concentration and accordingly furtherreduced ABR.

Determination of Efficacious Dose and Justification of AdministrationInterval Extension As doses to achieve the target exposure level of 45micro g/mL, once-weekly loading dose of 3 mg/kg for the first 4 weeksfollowed by once-weekly maintenance dose of 1.5 mg/kg oronce-every-two-week maintenance dose of 3 mg/kg were proposed. Therepeated loading doses were intended to achieve the steady-state plasmaconcentration as early as possible. The PopPK model-simulated plasmaemicizumab concentration-time profiles at the proposed dosing regimensare shown in FIG. 2 and FIG. 3 . The simulations indicated that morethan half of patients should achieve the target exposure level of 45micro g/mL at steady state (i.e., after 4 weeks onwards) at both dosingregimens.

Another proposed dosing regimen of once-weekly loading dose of 3 mg/kgfor the first 4 weeks followed by once-4-weekly maintenance dose of 6mg/kg was not predicted to achieve the target exposure level of 45 microg/mL as a median steady-state trough level, while providing a higherpeak level due to a larger peak-trough fluctuation (FIG. 4 ). However,in terms of efficacy, the PopPK/RTTE model-simulated ABR distributionswere predicted to be similar among the dosing regimens (FIG. 5 , FIG. 6, and FIG. 7 ). This suggests that with a given dose per administrationfor maintenance dose which is higher than that for loading dose,extending the administration interval would result in a similarbleeding-prophylactic efficacy to other dosing regimens with aper-administration maintenance dose lower than or equal to the loadingdose.

Example 2 A Randomized, Multi-Center, Open-Label Phase III ClinicalTrial to Evaluate the Efficacy, Safety and Pharmacokinetics ofProphylactic Emicizumab Versus No Prophylaxis in Hemophilia A PatientsWith Inhibitors (HAVEN 1)

This multicenter, open-label study evaluated the safety, efficacy andpharmacokinetics of prophylactic emicizumab treatment or regularemicizumab administration therapy in patients previously treated withepisodic or prophylactic bypassing agents. Episodic bypassing agentpatients were randomized in a 2:1 fashion to receive emicizumabprophylaxis (Arm A) versus no prophylaxis (Arm B) and were stratifiedacross Arms A and B according to the number of bleeds they hadexperienced over the last 24 weeks prior to study entry (less than [<] 9or greater than or equal to [>=] 9 bleeds); Arm B patients had theopportunity to switch to emicizumab prophylaxis after 24 weeks on-study.Prophylactic bypassing agent patients switched to emicizumab prophylaxis(Arm C) from the start of the trial; enrollment was extended for 24weeks after the last patient enrolled in Arms A or B or untilapproximately 50 patients enrolled in Arm C, whichever occurred first.Episodic or prophylactic bypassing agent patients who previouslyparticipated in a Non-Interventional Study (NIS) BH29768 but were unableto enroll in Arms A or B prior to their closure had the opportunity toenroll in Arm D until 24 weeks after the last patient enrolled in Arms Aor B or until approximately 35 patients enrolled in Arm D, whicheveroccurred first. Like patients in Arms A and C, Arm D patients receivedemicizumab prophylaxis from the start of the trial. All patientscontinued to receive standard of care/background treatment with theirusual episodic bypassing agent therapy to treat breakthrough bleeds, asneeded.

-   -   Arm A: Episodic Treatment+Study Drug (Emicizumab Prophylaxis)

Patients with inhibitors (patients that meet the inclusion criteria ofdiagnosis of congenital hemophilia A of any severity and documentedhistory of high-titer inhibitor (i.e., 5 or more Bethesda Units [BU]))who received episodic treatment with bypassing agents prior to studyentry were randomized to receive emicizumab prophylaxis when they startthe trial.

-   -   Arm B: Episodic Treatment (No Prophylaxis)

Patients with inhibitors who received episodic treatment with bypassingagents prior to study entry were randomized to continue episodicbypassing agent treatment when they start the trial; they had theopportunity to switch to emicizumab prophylaxis after 24 weeks on-study.

-   -   Arm C: Study Drug (Emicizumab Prophylaxis)+Episodic Treatment

Patients with inhibitors who received prophylactic treatment withbypassing agents prior to study entry received emicizumab prophylaxiswhen they start the trial.

-   -   Arm D: Study Drug (Emicizumab Prophylaxis)+Episodic Treatment

Episodic or prophylactic bypassing agent patients who previouslyparticipated in a Non-Interventional Study BH29768 but were unable toenroll in Arms A or B prior to their closure had the opportunity toenroll in Arm D, in which they received emicizumab prophylaxis when theystarted the trial.

Emicizumab was administered subcutaneously at a dose of 3 mg/kg/week for4 weeks followed by 1.5 mg/kg/week up to the end of the study.

The primary endpoint was the reduction of frequency in bleeding forpatients who received subcutaneously administered emicizumab at a doseof 3 mg/kg/week for 4 weeks followed by 1.5 mg/kg/week compared topatients without the drug. The number of bleeds was significantlyreduced in patients with the drug as described in more detail below.

Study Population

One hundred and nine participants were enrolled. All participants weremale and had a median age of 28 years (range, 12-75; Table 3); themedian age in Arm C was lower, which was consistent with higher prioruse of prophylactic BPAs in this younger group. While most had severehemophilia, 7/109 participants had mild or moderate disease.Approximately 40% of participants in Arms A, B, and D received priorimmune tolerance induction (ITT), while 67% of participants in Arm Cpreviously underwent ITI. The majority of participants (69.7%) hadtarget joints, with 69.7% having >1 target joint. Median (range)emicizumab treatment exposure was 24.0 weeks (3.0-47.9) overall. Median(range) duration of emicizumab treatment exposure were Arm A, 29.5(3.3-47.9) weeks; Arm B, 8.0 (4.0-16.0) weeks; Arm C, 19.0 (5.9-45.0)weeks and Arm D, 5.8 (3.0-14.0) weeks.

TABLE 3 Participant demographics and baseline characteristics Study armA: B: C: D: Emicizumab No Emicizumab Emicizumab prophylaxis prophylaxisprophylaxis prophylaxis Total (N = 35) (N = 18) (N = 49) (N = 7) (N =109) Sex, n (%) Male 35 (100) 18 (100) 49 (100) 7 (100) 109 (100) Age,years Median (min- 38.0 (12-68) 35.5 (13-65) 17.0 (12-75) 26.0 (19-49)28.0 (12-75) max) Age, n (%) <18 years 4 (11.4) 2 (11.1) 26 (53.1) 0 (0)32 (29.4) ≥18 years 31 (88.6) 16 (88.9) 23 (46.9) 7 (100) 77 (70.6)Hemophilia severity at baseline, n (%) Mild 2 (5.7) 0 (0) 1 (2.0) 0 (0)3 (2.8) Moderate 2 (5.7) 0 (0) 1 (2.0) 1 (14.3) 4 (3.7) Severe 31 (88.6)18 (100) 47 (95.9) 6 (85.7) 102 (93.6) Bleeding events in 24 weeks priorto study entry, n (%) <9 11 (31.4) 5 (27.8) 23 (46.9) 4 (57.1) 43 (39.4)≥9 24 (68.6) 13 (72.2) 26 (53.1) 3 (42.9) 66 (60.6) Target joints,* n(%) No 10 (28.6) 5 (27.8) 15 (30.6) 3 (42.9) 33 (30.3) Yes 25 (71.4) 13(72.2) 34 (69.4) 4 (57.1) 76 (69.7)   1 7 (28.0) 3 (23.1) 10 (29.4) 3(75.0) 23 (30.3) >1 18 (72.0) 10 (76.9) 24 (70.6) 1 (25.0) 53 (69.7)Highest historical inhibitor titer (BU) n 32 16 47 6 101 Mean (SD) 288.9(472.8) 706.8 (1450.0) 815.7 (1148.1) 528.9 (793.4) 614.5 (1037.9)Median 84.5 102.0 309.0 240.0 180.0 Min-Max 5-1570 18-4500 11-500028-2125 5-5000 <5 BU, n/N (%) 0/35 (0) 0/18 (0) 0/49 (0) 0/7 (0) 0/109(0) ≥5 BU, n/N (%) 32/35 (91.4) 16/18 (88.9) 47/49 (95.9) 6/7 (85.7)101/109 (92.7) Unknown, n/N 3/35 (8.6) 2/18 (11.1) 2/49 (4.1) 1/7 (14.3)8/109 (7.3) (%) Episodic coagulation product use in 24 weeks prior tostudy entry, n (%) Any products 35 (100) 18 (100) 23 (47) 7 (100) 83(76) aPCC 27 (77.1) 13 (72.2) 15 (65.2) 5 (71.4) 60 (72.3) rFVIIa 22(62.9) 17 (94.4) 15 (65.2) 5 (71.4) 59 (71.1) Factor VIII 1 (2.9) 0 (0)1 (4.3) 2 (28.6) 4 (4.8) Other 1 (2.9) 0 (0) 0 (0) 1 (14.3) 2 (2.4)Prophylactic coagulation product use in 24 weeks prior to study entry, n(%) Any products 0 (0) 0 (0) 49 (100) 0 (0) 49 (45) aPCC 0 (0) 0 (0) 36(73.5) 0 (0) 36 (73.5) rFVIIa 0 (0) 0 (0) 15 (30.6) 0 (0) 15 (30.6)Factor VIII 0 (0) 0 (0) 1 (2.0) 0 (0) 1 (2.0) Other 0 (0) 0 (0) 1 (2.0)0 (0) 1 (2.0) *% based on number of participants with target joints, allnumbers are based on eCRF and not NIS data. aPCC, activated prothrombincomplex concentrates; NIS, non-interventional study; rFVIIa, recombinantfactor VIIa.

Efficacy

There was a statistically significant and clinically meaningful 87%reduction in bleed rates between Arms A (emicizumab prophylaxis) versusB (no prophylaxis); ABR (95% CI) 2.9 (1.69; 5.02) versus 23.3 (12.33;43.89), p<0.0001 (FIG. 8 and Table 4). Statistically significant andclinically meaningful reductions were also observed in all secondarybleed-related endpoints, including spontaneous, joint, and target jointbleeds, and all bleeds. Overall, 62.9% (22/35) of participantsrandomized to emicizumab prophylaxis experienced zero bleeds (FIG. 8 andTable 4).

TABLE 4 Bleeds across study arms Study arms A: Emicizumab B: No C:Emicizumab prophylaxis prophylaxis prophylaxis Bleeds (N = 35) (N = 18)(N = 49) Treated bleeds (with BPAs) ABR, model based^(a) (95% CI)  2.9(1.69; 5.02) 23.3 (12.33; 43.89) 5.1 (2.28; 11.22) % reduction (RR), pvalue 87% (0.13), p < 0.0001 — Median ABR, calculated (IQR) 0.0 (0.0;3.7)  18.8 (13.0; 35.1)  0.0 (0.0; 1.7)   All bleeds (treated/ nottreated with BPAs) ABR, model based^(a) (95% CI)  5.5 (3.58; 8.60) 28.3(16.79; 47.76) 6.5 (3.43; 12.43) % reduction (RR), p value 80% (0.20), p< 0.0001 — Median ABR, calculated (IQR) 2.0 (0.0; 9.9)  30.2 (18.3;39.4)  0.0 (0.0; 6.0)   Treated spontaneous bleeds ABR, model based^(a)(95% CI)  1.3 (0.73; 2.19) 16.8 (9.94; 28.30)  3.1 (1.20; 8.02)  %reduction (RR), p value 92% (0.08), p < 0.0001 — Median ABR, calculated(IQR) 0.0 (0.0; 3.3)  15.2 (6.6; 30.4)   0.0 (0.0; 0.0)   Treated jointbleeds ABR, model based^(a) (95% CI)  0.8 (0.26; 2.20) 6.7 (1.99; 22.42)0.6 (0.21; 1.48)  % reduction (RR), p value 89% (0.1), 0.0050 — MedianABR, calculated (IQR) 0.0 (0.0; 0.0)  1.0 (0.0; 14.4)  0.0 (0.0; 0.0)  Treated target joint bleeds ABR, model based^(a) (95% CI)  0.1 (0.03;0.58) 3.0 (0.96; 9.13)  0.3 (0.10; 0.95)  % reduction (RR), p value 95%(0.05), 0.0002 — Median ABR, calculated (IQR) 0.0 (0.0; 0.0)  1.0 (0.0;6.5)   0.0 (0.0; 0.0)   Participants with zero bleeds, 62.9 (44.9; 78.5)5.6 (0.1; 27.3)  69.4 (54.6; 81.7)  % (95% CI) ^(a)Negative binomialmodel. ABR, annualized bleeding rate; BPA, bypassing agent; CI,confidence interval; IQR, interquartile range; RR, relative risk

The intra-participant comparison in those who had previouslyparticipated in the NIS showed that emicizumab prophylaxis significantlyreduced bleed rate versus previous BPA prophylaxis (79%: RR 0.21;p=0.0003 [Arm C]); individual participant data are shown in FIG. 9 andcorresponding data for the intra-participant comparison versus priorepisodic BPAs (Arm A) are shown in FIG. 11 . Intra-participantcomparison for emicizumab prophylaxis versus prior episodic BPAtreatment showed a significant reduction in the risk of treated bleeds(92%: RR 0.08; p<0.0001 [Arm A]).

Emicizumab prophylaxis was associated with statistically significant andclinically meaningful improvements in health-related quality of life(HRQoL) and health status compared with no prophylaxis. Differences inadjusted means observed in study and clinically important differencesdetermined from published literature (Wyrwich et al. Interpretingimportant health-related quality of life change using the Haem-A-QoL.Haemophilia. 2015;21(5):578-584; Walters and Brazier. Comparison of theminimally important difference for two health state utility measures:EQ-5D and SF-6D. Qual Life Res. 2005;14(6):1523-1532.; Pickard et al.Estimation of minimally important differences in EQ-5D utility and VASscores in cancer. Health Qual Life Outcomes. 2007;5:70), respectively,were as follows: Haem-A-QoL physical health subscale, 21.55 (p=0.0029)and 10 points; Haem-A-QoL total score, 14.01 (p=0.0019) and 7 points;EQ-5D-5L VAS, −9.72 (p=0.0171) and 7 points; and, EQ-5D-5L Index utilityscore, −0.16 (p=0.0014) and 0.07 points.

Pharmacokinetic and Pharmacodynamic Outcomes

Mean trough emicizumab concentrations of >50 micro g/mL in blood wereachieved after 4 weeks with administrations of the loading dose of 3mg/kg/week, and sustained over the course of the study withadministrations of the maintenance dose of 1.5 mg/kg/week (FIG. 10 ).D-dimer and prothrombin fragment 1.2 were not affected by emicizumabtreatment.

Example 3 Efficacy, Safety and Pharmacokinetics (PK) of Once-WeeklyProphylactic (Px) Emicizumab (ACE910) in Pediatric (<12 Years) PersonsWith Hemophilia A With Inhibitors (PwHAwI): Interim Analysis ofSingle-Arm, Multicenter, Open-Label, Phase 3 Study (HAVEN 2)

The study enrolled PwHAwI aged <12 years (or 12-17 years if <40 kg)previously treated with bypassing agents (BPAs) to receive emicizumabprophylaxis for 52 or more weeks. Efficacy objectives includedannualized bleeding rate (ABR) and bleed reduction versus historicalbleed rate (non-interventional study).

Participants received weekly subcutaneous (SC) administrations ofemicizumab for a designated period of 52 weeks. All participantscontinued to receive standard of care/background treatment with theirusual episodic bypassing agent therapy to treat breakthrough bleeds asneeded.

Emicizumab was administered SC once weekly for 52 weeks, 3 milligramsper kilogram per week (mg/kg/week) for 4 weeks and 1.5 mg/kg/weekthereafter. The regimen was to be adapted based upon efficacy/bleedcontrol.

Interim analysis included 20 PwHAwI aged 3-12 years (median 8.5); 19aged <12 years were included in the efficacy analyses (Table 5). Themedian observation time was 12.1 weeks (range 7.1-14.1). In total, 18/19(94.7%) PwHAwI had zero treated bleeds and 12/19 (63.2%) did not bleedwhile on study. Overall, 14 bleeds were reported in 7 PwHAwI; with noneoccurring in a joint or muscle. A substantial reduction in ABR on studyversus ABR from the NIS was observed in 8 PwHAwI included in theintra-participant comparison (FIG. 12 ); 8/8 had 100% reduction innumber of treated bleeds, 5/8 had 100% reduction in number of allbleeds, and all PwHAwI had >75% reduction of all bleeds. Mean troughemicizumab concentrations of >50 micro g/mL were achieved after 4 weeksand sustained.

Emicizumab Px (prophylaxis) was safe and prevented/reduced bleeds inpediatric PwHAwI, showing clinically meaningful reductions in ABRcompared with historical ABR. PK was similar to that seen in adult PwHA(persons with hemophilia A). These interim data show the potential foremicizumab to reduce the treatment and disease burden for pediatricPwHAwI.

TABLE 5 Bleeding events in HAVEN 2 study Mean ABR^(b) % PwHAwI with zero(95% CI) bleeds (95% CI) Bleeds^(a) N = 10 N = 19 Treated bleeds 0.4(0.00; 4.51) 94.7 (74.0; 99.9) All bleeds 3.7 (0.94; 9.81) 63.2 (38.4;83.7) Treated spontaneous bleeds 0.4 (0.00; 4.51) 94.7 (74.0; 99.9)^(a)Bleed/medication questionnaire completed by caregiver via anelectronic handheld device. Bleed definitions based on ISTH criteria(Blanchette V S, et al. J Thromb Haemost 2014; 12: 1935-39). Treatedbleeds: bleeds treated with BPAs. All bleeds: bleeds treated and nottreated with BPAs. ^(b)ABR calculated for persons on HAVEN 2 study 12 ormore weeks.

Example 4 A Randomized, Multi-Center, Open-Label, Phase 3 Clinical Studyin Participants Aged 12 Years or Older to Evaluate the Efficacy, Safety,and Pharmacokinetics of Prophylactic Emicizumab Versus No Prophylaxis inParticipants With Severe Hemophilia A Without Inhibitors Against FVIII(HAVEN 3)

This is a randomized, multicenter, open-label, Phase 3 clinical study inparticipants aged 12 years or older to evaluate the efficacy, safety,and pharmacokinetics of prophylactic emicizumab versus no prophylaxis inparticipants with severe hemophilia A without inhibitors against FVIII(HAVEN 3).

Participants received emicizumab prophylaxis at the specified dosesubcutaneously until the end of the study (maximum up to 2 years).

-   -   Experimental: Emicizumab (pre-study FVIII prophylaxis)

Participants who received FVIII prophylaxis prior to study entryreceived emicizumab prophylaxis at a dose of 3 mg/kg/week subcutaneouslyfor 4 weeks, followed by 1.5 milligram per kilogram per week(mg/kg/week) emicizumab subcutaneously until the end of study (maximumup to 2 years).

-   -   Experimental: Emicizumab 1.5 mg/kg/week

Participants who received episodic treatment with FVIII prior to studyentry received emicizumab prophylaxis at a dose of 3 mg/kg/weeksubcutaneously for 4 weeks, followed by 1.5 mg/kg/week emicizumabsubcutaneously until the end of study (maximum up to 2 years).

-   -   Experimental: Emicizumab 3 mg/kg/2 weeks Participants who        received episodic treatment with FVIII prior to study entry        received emicizumab prophylaxis at a dose of 3 mg/kg/week        subcutaneously for 4 weeks, followed by 3 mg/kg once every 2        weeks (3 mg/kg/2 weeks) emicizumab subcutaneously until the end        of study (maximum up to 2 years).    -   Active Comparator: No prophylaxis

Participants who received episodic treatment with FVIII prior to studyentry were randomized to continue episodic FVIII treatment when theystarted the trial; they had the opportunity to switch to emicizumabprophylaxis after 24 weeks on-study.

Primary Outcome Measures:

Number of bleeds over time

Secondary Outcome Measures:

Reduction in number of bleeds over time [Time Frame: Baseline, 24 weeks]

Reduction in number of joint bleeds over time [Time Frame: Baseline, 24weeks]

Reduction in number of target joint bleeds over time [Time Frame:Baseline, 24 weeks]

Health related quality of life scores [Time Frame: 24 weeks]

Trough plasma concentration (C_(trough)) of emicizumab [Time Frame:(Pre-dose) Every week during Weeks 1-4, every 2 weeks during Weeks 5-8,every 4 weeks during Weeks 9-24, every 8 weeks during Weeks 25-48, every12 weeks thereafter (maximum up to 2 years)]

Example 5 A Multicenter, Open-Label, Non-Randomized Study to Assess theEfficacy, Safety, Pharmacokinetics, and Pharmacodynamics of EmicizumabAdministered at a Dose of 6 Milligrams Per Kilogram (mg/kg) Every 4Weeks in Participants With Hemophilia A With or Without InhibitorsAgainst FVIII (HAVEN 4)

This multicenter, open-label, non-randomized study has assessed theefficacy, safety, pharmacokinetics, and pharmacodynamics of emicizumabadministered at a dose of 6 milligrams per kilogram (mg/kg) once every 4weeks (Q4W) in participants with hemophilia A with or without inhibitorsagainst factor VIII (FVIII). The study consisted of 2 parts: apharmacokinetic (PK) run-in part followed by an expansion part.

Emicizumab was administered according to the dose and schedule describedin respective arms.

-   -   Experimental: Emicizumab: Expansion Part

Participants received emicizumab at a loading dose of 3 mg/kg once everyweek subcutaneously for initial 4 weeks followed by a maintenance doseof 6 mg/kg once every 4 weeks subcutaneously for a minimum of 24 weeks.

-   -   Experimental: Emicizumab: PK Run-in Part

Participants received emicizumab at a dose of 6 mg/kg once every 4 weekssubcutaneously for a minimum of 24 weeks.

Primary Outcome Measures:

Expansion Part: Number of Bleeding Events Over Time [Time Frame:Expansion Part: Day 1 up to Study Completion (a Minimum of 24 Weeks, Upto Approximately 20 Months)]

At the data cutoff of Apr. 10, 2017, 7 patients with severe hemophilia Ahad enrolled into the PK run-in cohort, 4 patients without inhibitorsand 3 patients with inhibitors, of which 6 patients were aged 18 andover, and followed for a minimum of 6 weeks. Individual observed PKprofiles were within the 95% prediction interval computed from apopulation PK model based on clinical data from a 1.5 mg/kg QW regimen(FIG. 13 : gray bold solid lines indicate the upper and lower limits ofthe 95% prediction interval). Emicizumab PK parameters derived after asingle SC administration of 6 mg/kg emicizumab (Table 6) were consistentwith the values observed in previous studies with emicizumab (Uchida etal. Blood 2016; 127 (13):1633-1641). During the observation period(median, 8 weeks), 14 adverse events (AEs) were reported in 5 patientsat the time of data cut-off, including 1 Grade 3 serious AE (worseningof hypertension); no AEs were considered related to the study drug. Noanti-drug antibodies were detected. Also, 6 out of 7 patients had nobleeds while receiving Q4W emicizumab; 1 patient experienced 3spontaneous nose bleeds on Study Days 12, 14, and 21, which did notrequire treatment.

TABLE 6 Summary of PK parameters after single SC dose of 6 mg/kgemicizumab T_(max) C_(max) AUC_(Day28) T_(1/2) (day) (μg/mL) (day *μg/mL) (day) Value* 6.95 (3.99-7.18) 31.8 (19.3) 662.5 (19.7) 30.2(35.8) *Median (range) for T_(max) and geometric mean (CV %) for allother parameters.

Preliminary data from the HAVEN 4 study showed that Q4W dosing ofemicizumab at 6 mg/kg per administration exhibited a PK behavior thatwas consistent with prior predictions, leading to an expectedsteady-state concentration average similar to the clinically confirmeddosing regimen (i.e., 1.5 mg/kg/QW). The safety and efficacy resultsfrom this PK run-in cohort enabled the opening of the HAVEN 4 expansioncohort, and provided promising support for a Q4W emicizumab prophylaxisregimen for the management of hemophilia A. The HAVEN 4 study is fullyenrolled (N=48, including the PK run-in cohort patients).

Example 6 A Multicenter, Open-Label, Phase III Clinical Trial toEvaluate the Efficacy, Safety, and Pharmacokinetics of SubcutaneousAdministration of Emicizumab in Hemophilia A Pediatric Patients WithInhibitors

The study protocol of HAVEN 2 (see Example 3) has been amended toevaluate additional two emicizumab dosing schedules (once every 2 weeks[Q2W] and once every 4 weeks [Q4W]) as well as the originally planneddosing schedule (once weekly [QW]).

Overall, this non-randomized, multicenter, open-label, Phase IIIclinical study enrolls children with hemophilia A who have inhibitorsagainst FVIII. Children with hemophilia A and documented historicalFVIII inhibitor titer (5 BU or more) must currently be receivingtreatment with bypassing agents. The study enrolls at least 40 patientsyounger than 12 years of age and up to approximately 80 patients, withallowance of patients of 12 to 17 years of age who weigh less than 40 kgat the time of informed consent.

Patients enrolled in Cohort A receive emicizumab administration, with aloading dose of 3 mg/kg per administration once weekly (QW) for thefirst 4 weeks and a maintenance dose of 1.5 mg/kg per administration QWthereafter for a minimum of 52 weeks in total. Patients enrolled inCohorts B and C receive emicizumab administration, with the same loadingdose of 3 mg/kg QW for the first 4 weeks and a maintenance dose of 3mg/kg Q2W (Cohort B) or 6 mg/kg Q4W (Cohort C) thereafter for a minimumof 52 weeks in total. During the 52-week treatment period, individualpatients may have their dose up-titrated if they experience suboptimalbleeding control with emicizumab.

The efficacy analyses evaluate the clinical effect of prophylacticemicizumab on the number of bleeds over time (i.e., bleed rate), andcharacterize the efficacy of up-titration on an intra-patient level.Bleeds having different bleed definitions such as treated bleeds, allbleeds, treated spontaneous bleeds, treated joint bleeds, and treatedtarget joint bleeds are analyzed separately.

The primary analysis is performed 52 weeks after the last patient in theprimary cohort, which consists of all patients enrolled in Cohort Aprior to the close of enrollment for patients 2 years of age or older,has been enrolled or withdrawn prematurely, whichever occurs first. Noformal hypothesis testing is planned in the study.

Results from an interim analysis in Cohort A are presented in Example 3.

Example 7 A Multicenter, Open-Label, Phase III Study Evaluating theEfficacy, Safety, and Pharmacokinetics of Emicizumab Administered Every2 or 4 Weeks in Pediatric Patients Less Than 12 Years Old WithHemophilia A Without Factor VIII Inhibitors

This study is a multicenter, open-label, non-randomized study designedto evaluate the efficacy, safety, and pharmacokinetics of emicizumabadministered subcutaneously at a dose of 3 mg/kg per administration onceevery 2 weeks (Q2W cohort) or 6 mg/kg per administration once every 4weeks (Q4W cohort) in pediatric patients with hemophilia A withoutinhibitors. The study enrolls a minimum of 6 patients less than 12 yearsold with hemophilia A without inhibitors in each cohort.

The Q2W cohort of the study receives a loading dose of 3 mg/kg ofemicizumab administered subcutaneously once weekly (QW) for the first 4doses, followed by a maintenance dose of 3 mg/kg administeredsubcutaneously once every 2 weeks (Q2W) for at least 24 weeks in total.The Q4W cohort receives a loading dose of 3 mg/kg of emicizumabadministered subcutaneously once weekly (QW) for the first 4 doses,followed by a maintenance dose of 6 mg/kg administered subcutaneouslyonce every 4 weeks (Q4W) for at least 24 weeks in total. After Week 12of emicizumab treatment, a higher dose may be selected for patients whomeet the insufficient bleeding control criteria.

The efficacy analyses evaluate the clinical effects of emicizumabprophylaxis based on the bleeding frequency (bleeding rate) during aspecified period. Bleeds having various different definitions such asbleeds requiring use of coagulation factors for hemostasis, spontaneousbleeds, joint bleeds, target joint bleeds, and all bleeds are analyzedseparately. The primary efficacy analysis is conducted in each cohortwhen all patients have completed the 24-week treatment or have beenwithdrawn from the study, whichever occurs first. No statisticalhypothesis testing is planned.

[Sequence Listing]

1. A method for treating and/or reducing the incidence of a disease thatdevelops and/or progresses due to a decrease or deficiency in theactivity of blood coagulation factor VIII and/or activated bloodcoagulation factor VIII (FVIIIa), the method comprising: administeringto a subject a bispecific antibody that recognizes (a) blood coagulationfactor IX and/or activated blood coagulation factor IX and (b) bloodcoagulation factor X and/or activated blood coagulation factor X at aweekly loading dose of 3 mg/kg or 4.5 mg/kg of the antibody for one ormore weeks or at an every-two-week loading dose of 6 mg/kg of theantibody for two or more weeks; and, after the loading doseadministration(s) are complete, administering a maintenance dose of theantibody to the subject one or more times, the maintenance dose being 6mg/kg of the antibody.
 2. The method of claim 1, wherein the maintenancedose of 6 mg/kg of the antibody is administered to the subject everyfour weeks or every month in a single dose or multiple divided doses. 3.The method of claim 1 or 2, wherein the antibody is administered at theweekly loading dose of 3 mg/kg of the antibody for four weeks, followedby the maintenance dose.
 4. The method of claim 1 or 2, wherein theantibody is administered at the weekly loading dose of 4.5 mg/kg of theantibody for two weeks, followed by the maintenance dose.
 5. The methodof claim 1 or 2, wherein the antibody is administered at theevery-two-week loading dose of 6 mg/kg of the antibody for four weeks,followed by the maintenance dose.
 6. The method of any one of claims 1to 5, wherein the maintenance dose is administered in one single dose at6 mg/kg of the antibody monthly or every four weeks.
 7. The method ofany one of claims 1 to 5, wherein the maintenance dose is administeredin two single doses of the antibody, each at 3 mg/kg, monthly or everyfour weeks, wherein one single dose of the maintenance dose at 3 mg/kgof the antibody is administered once every two weeks.
 8. The method ofany one of claims 1 to 5, wherein the maintenance dose is administeredin four single doses each at 1.5 mg/kg of the antibody monthly or everyfour weeks, wherein one single dose of the maintenance dose at 1.5 mg/kgof the antibody is administered once every week.
 9. The method of anyone of claims 1 to 8 further comprising, in a case of no or insufficienteffect of treating and/or reducing the incidence of the disease byadministering the maintenance dose of the antibody, stoppingadministering the maintenance dose of the antibody and startingadministering an alternative maintenance dose of the antibody to thesubject, the alternative maintenance dose being a weekly dose of 3 mg/kgof the antibody or an every-two-week dose of 6 mg/kg of the antibody.10. A method for treating and/or reducing the incidence of a diseasethat develops and/or progresses due to a decrease or deficiency in theactivity of blood coagulation factor VIII and/or activated bloodcoagulation factor VIII (FVIIIa), the method comprising: administeringto a subject a bispecific antibody that recognizes (a) blood coagulationfactor IX and/or activated blood coagulation factor IX and (b) bloodcoagulation factor X and/or activated blood coagulation factor X at aweekly loading dose of 4.5 mg/kg of the antibody for four weeks; andthereafter administering a maintenance dose of the antibody to thesubject one or more times, the maintenance dose being 9 mg/kg of theantibody which is administered every four weeks or every month in two orfour divided doses.
 11. A method for treating and/or reducing theincidence of a disease that develops and/or progresses due to a decreaseor deficiency in the activity of blood coagulation factor VIII and/oractivated blood coagulation factor VIII (FVIIIa), the method comprising:administering to a subject a bispecific antibody that recognizes (a)blood coagulation factor IX and/or activated blood coagulation factor IXand (b) blood coagulation factor X and/or activated blood coagulationfactor X at a weekly loading dose of 6 mg/kg of the antibody for fourweeks; and thereafter administering a maintenance dose of the antibodyto the subject one or more times, the maintenance dose being 12 mg/kg ofthe antibody which is administered every four weeks or every month intwo or four divided doses.
 12. The method of claim 10 furthercomprising, in a case of no or insufficient effect of treating and/orreducing the incidence of the disease by administering the maintenancedose of the antibody, stopping administering the maintenance dose of theantibody and starting administering an alternative maintenance dose ofthe antibody to the subject, the alternative maintenance dose being aweekly dose of 4.5 mg/kg of the antibody.
 13. The method of claim 11further comprising, in a case of no or insufficient effect of treatingand/or reducing the incidence of the disease by administering themaintenance dose of the antibody, stopping administering the maintenancedose of the antibody and starting administering an alternativemaintenance dose of the antibody to the subject, the alternativemaintenance dose being a weekly dose of 6 mg/kg of the antibody.
 14. Themethod of any one of claims 1 to 13, wherein the antibody is emicizumab.15. The method of claim 14, wherein the disease that develops and/orprogresses due to a decrease or deficiency in the activity of bloodcoagulation factor VIII and/or activated blood coagulation factor VIIIis selected from the group consisting of hemophilia A, acquiredhemophilia A, von Willebrand disease, and hemophilia A with emergence ofan inhibitor against blood coagulation factor VIII and/or activatedblood coagulation factor VIII.